Bicyclic compounds

ABSTRACT

Disclosed herein are compounds of Formulae (I) and (II), methods of synthesizing compounds of Formulae (I) and (II), and methods of using compounds of Formulae (I) and (II) as an analgesic.

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

Any and all applications for which a foreign or domestic priority claimis identified, for example, in the Application Data Sheet or Request asfiled with the present application, are hereby incorporated by referenceunder 37 CFR 1.57, and Rules 4.18 and 20.6.

BACKGROUND

1. Field

The present application relates to the fields of chemistry, biochemistryand medicine. More particularly, disclosed herein are bicyclopentanecompounds. Also disclosed herein are methods of using bicyclopentanecompounds as an analgesic.

2. Description

Nonsteroidal anti-inflammatory compounds, or NSAIDs, are an extremelyuseful group of small molecule drugs, typified by acetylsalicylic acid,ibuprofen and naproxen. These are often sold without prescription, andare variously used to treat pain, inflammation, and fever. However,NSAIDs can have undesirable side effects, including gastric upset and/orgastric bleeding.

Acetaminophen, also known as paracetamol or APAP, is also an effectivepain reliever often sold over the counter (without prescription).Although it shares analgesic and antipyretic properties with NSAIDs, ithas only weak anti-inflammatory properties, and is thus not an NSAID.Unlike many NSAIDs, acetaminophen does not cause gastric upset orbleeding in prescribed doses. Thus, it is an extremely useful drug forthose wishing analgesia without adverse gastric side effects.

Acetaminophen has the structure:

Acetaminophen is often combined with other drugs for relief of symptomsof influenza and the common cold, among other indications. It isparticularly useful in combination with opioid analgesics, where itexhibits synergistic analgesic properties and allows patients to achieveadequate pain relief with lower doses of opioids. The most widelyprescribed drug in the United States is a combination of acetaminophenand hydrocodone, with over 130 million prescriptions in the year 2010.Other acetaminophen-opioid combinations, including combinations withoxycodone, are also widely prescribed.

Acetaminophen poisoning is the most common cause of acute liver failurein the Western world, and acetaminophen accounts for the most drugoverdoses in the English-speaking world. Acetaminophen is metabolized toform N-acetyl-p-benzoquinoneimine (NAPQI), which depletes glutathione inthe liver, and if the glutathione is sufficiently depleted, as is thecase with an acetaminophen overdose, the NAPQI metabolite injureshepatocytes leading to acute liver failure and often death. Theacetaminophen-opioid combination drugs are commonly implicated in suchtoxicity, for various reasons. First, patients might not recognize thatthe prescribed pain relievers contain acetaminophen, and may supplementwith acetaminophen if pain relief is inadequate. Second, continuedadministration of opioids can lead to tolerance and the need forincreased dosages to obtain a comparable opioid effect, and users orabusers of the combination drugs may exceed safe dosages ofacetaminophen as a consequence.

This has led the U.S. FDA to seek reduced amounts of acetaminophen inthe opioid combination drugs and has also led an FDA advisory panel torecommend banning such drugs all together. Although theacetaminophen-opioid drugs remain on the market, there is a strong needfor a less toxic replacement without the same hepatotoxicity risks.

SUMMARY

Some embodiments described herein relate to a compound of Formula (I),or a pharmaceutically acceptable salt thereof. Other embodimentsdescribed herein relate to a compound of Formula (II), or apharmaceutically acceptable salt thereof.

Some embodiments described herein related to a pharmaceuticalcomposition that can include an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof. Otherembodiments described herein related to a pharmaceutical compositionthat can include an effective amount of a compound of Formula (II), or apharmaceutically acceptable salt thereof.

Some embodiments described herein related to using a compound of Formula(I), or a pharmaceutically acceptable salt thereof, in the preparationof a medicament for reducing or at least partially preventing painand/or fever. Other embodiments described herein related to a method forreducing or at least partially preventing pain and/or fever that caninclude administering an effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, to a subject in needthereof. Still other embodiments described herein related to a methodfor reducing or at least partially preventing pain and/or fever that caninclude contacting a cell in the central and/or peripheral nervoussystem of a subject with an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, to a subject in needthereof. Yet still other embodiments described herein related to the useof a compound of Formula (I), or a pharmaceutically acceptable saltthereof, for reducing or at least partially preventing pain and/orfever.

Some embodiments described herein related to using a compound of Formula(II), or a pharmaceutically acceptable salt thereof, in the preparationof a medicament for reducing or at least partially preventing painand/or fever. Other embodiments described herein related to a method forreducing or at least partially preventing pain and/or fever that caninclude administering an effective amount of a compound of Formula (II),or a pharmaceutically acceptable salt thereof, to a subject in needthereof. Still other embodiments described herein related to a methodfor reducing or at least partially preventing pain and/or fever that caninclude contacting a cell in the central and/or peripheral nervoussystem of a subject with an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, to a subject in needthereof. Yet still other embodiments described herein related to the useof a compound of Formula (II), or a pharmaceutically acceptable saltthereof, for reducing or at least partially preventing pain and/orfever.

DETAILED DESCRIPTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there are aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise.

Whenever a group is described as being “optionally substituted” thatgroup may be unsubstituted or substituted with one or more of theindicated substituents. Likewise, when a group is described as being“unsubstituted or substituted” if substituted, the substituent(s) may beselected from one or more the indicated substituents. If no substituentsare indicated, it is meant that the indicated “optionally substituted”or “substituted” group may be substituted with one or more group(s)individually and independently selected from alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl,aryl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy,acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl,O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato,isothiocyanato, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl,haloalkoxy, an amino, a mono-substituted amino group and adi-substituted amino group.

As used herein, “C_(a) to C_(b)” in which “a” and “b” are integers referto the number of carbon atoms in a group. The indicated group cancontain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a“C₁ to C₄ alkyl” group refers to all alkyl groups having from 1 to 4carbons, that is, CH₃—, CH₃CH₂—, CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—,CH₃CH₂CH(CH₃)— and (CH₃)₃C—. If no “a” and “b” are designated, thebroadest range described in these definitions is to be assumed.

If two “R” groups are described as being “taken together” the R groupsand the atoms they are attached to can form a cycloalkyl, cycloalkenyl,aryl, heteroaryl or heterocycle. For example, without limitation, ifR^(a) and R^(b) of an NR^(a) R^(b) group are indicated to be “takentogether,” it means that they are covalently bonded to one another toform a ring:

As used herein, the term “alkyl” refers to a fully saturated aliphatichydrocarbon group. The alkyl moiety may be branched or straight chain.Examples of branched alkyl groups include, but are not limited to,iso-propyl, sec-butyl, t-butyl and the like. Examples of straight chainalkyl groups include, but are not limited to, methyl, ethyl, n-propyl,n-butyl, n-pentyl, n-hexyl, n-heptyl and the like. The alkyl group mayhave 1 to 30 carbon atoms (whenever it appears herein, a numerical rangesuch as “1 to 30” refers to each integer in the given range; e.g., “1 to30 carbon atoms” means that the alkyl group may consist of 1 carbonatom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30carbon atoms, although the present definition also covers the occurrenceof the term “alkyl” where no numerical range is designated). The alkylgroup may also be a medium size alkyl having 1 to 12 carbon atoms. Thealkyl group could also be a lower alkyl having 1 to 6 carbon atoms. Analkyl group may be substituted or unsubstituted.

The term “alkenyl” used herein refers to a monovalent straight orbranched chain radical of from two to twenty carbon atoms containing acarbon double bond(s) including, but not limited to, 1-propenyl,2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like. Analkenyl group may be unsubstituted or substituted.

The term “alkynyl” used herein refers to a monovalent straight orbranched chain radical of from two to twenty carbon atoms containing acarbon triple bond(s) including, but not limited to, 1-propynyl,1-butynyl, 2-butynyl and the like. An alkynyl group may be unsubstitutedor substituted.

As used herein, “cycloalkyl” refers to a completely saturated (no doubleor triple bonds) mono- or multi-cyclic hydrocarbon ring system. Whencomposed of two or more rings, the rings may be joined together in afused, bridged or spiro fashion. Cycloalkyl groups can contain 3 to 30atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in thering(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). Acycloalkyl group may be unsubstituted or substituted. Typicalmono-cycloalkyl groups include, but are in no way limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl. Examples of fused cycloalkyl groups aredecahydronaphthalenyl, dodecahydro-1H-phenalenyl andtetradecahydroanthracenyl; and examples of bridged cycloalkyl groups arebicyclo[1.1.1]pentyl, adamantanyl and norbornanyl.

As used herein, “cycloalkenyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more double bonds in atleast one ring; although, if there is more than one, the double bondscannot form a fully delocalized pi-electron system throughout all therings (otherwise the group would be “aryl,” as defined herein).Cycloalkenyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in thering(s) or 3 to 6 atoms in the ring(s). When composed of two or morerings, the rings may be connected together in a fused, bridged or spirofashion. A cycloalkenyl group may be unsubstituted or substituted.

As used herein, “cycloalkynyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more triple bonds in atleast one ring. If there is more than one triple bond, the triple bondscannot form a fully delocalized pi-electron system throughout all therings. Cycloalkynyl groups can contain 8 to 30 atoms in the ring(s), 8to 20 atoms in the ring(s) or 8 to 10 atoms in the ring(s). Whencomposed of two or more rings, the rings may be joined together in afused, bridged or spiro fashion. A cycloalkynyl group may beunsubstituted or substituted.

As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclicor multicyclic aromatic ring system (including fused ring systems wheretwo carbocyclic rings share a chemical bond) that has a fullydelocalized pi-electron system throughout all the rings. The number ofcarbon atoms in an aryl group can vary. For example, the aryl group canbe a C₆-C₁₄ aryl group, a C₆-C₁₀ aryl group, or a C₆ aryl group.Examples of aryl groups include, but are not limited to, benzene,naphthalene and azulene. An aryl group may be substituted orunsubstituted.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system (a ring system with fully delocalized pi-electronsystem) that contain(s) one or more heteroatoms (for example, 1, 2 or 3heteroatoms), that is, an element other than carbon, including but notlimited to, nitrogen, oxygen and sulfur. The number of atoms in thering(s) of a heteroaryl group can vary. For example, the heteroarylgroup can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in thering(s) or 5 to 6 atoms in the ring(s). Furthermore, the term“heteroaryl” includes fused ring systems where two rings, such as atleast one aryl ring and at least one heteroaryl ring, or at least twoheteroaryl rings, share at least one chemical bond. Examples ofheteroaryl rings include, but are not limited to, furan, furazan,thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole,1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole,1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole,indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole,isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline,isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. Aheteroaryl group may be substituted or unsubstituted.

As used herein, “heterocyclyl” or “heteroalicyclyl” refers to three-,four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-memberedmonocyclic, bicyclic and tricyclic ring system wherein carbon atomstogether with from 1 to 5 heteroatoms constitute said ring system. Aheterocycle may optionally contain one or more unsaturated bondssituated in such a way, however, that a fully delocalized pi-electronsystem does not occur throughout all the rings. The heteroatom(s) is anelement other than carbon including, but not limited to, oxygen, sulfurand nitrogen. A heterocycle may further contain one or more carbonyl orthiocarbonyl functionalities, so as to make the definition includeoxo-systems and thio-systems such as lactams, lactones, cyclic imides,cyclic thioimides and cyclic carbamates. When composed of two or morerings, the rings may be joined together in a fused or spiro fashion.Additionally, any nitrogens in a heteroalicyclic may be quaternized.Heterocyclyl or heteroalicyclic groups may be unsubstituted orsubstituted. Examples of such “heterocyclyl” or “heteroalicyclyl” groupsinclude but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane,1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane,1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane,1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide,succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine,hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine,imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline,oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine,oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine,pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine,2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran,thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone andtheir benzo-fused analogs (e.g., benzimidazolidinone,tetrahydroquinoline and/or 3,4-methylenedioxyphenyl).

As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl groupconnected, as a substituent, via a lower alkylene group. The loweralkylene and aryl group of an aralkyl may be substituted orunsubstituted. Examples include but are not limited to benzyl,2-phenylalkyl, 3-phenylalkyl and naphthylalkyl.

As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to aheteroaryl group connected, as a substituent, via a lower alkylenegroup. The lower alkylene and heteroaryl group of heteroaralkyl may besubstituted or unsubstituted. Examples include but are not limited to2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl,pyridylalkyl, isoxazolylalkyl and imidazolylalkyl and their benzo-fusedanalogs.

A “heteroalicyclyl(alkyl)” and “heterocyclyl(alkyl)” refer to aheterocyclic or a heteroalicyclylic group connected, as a substituent,via a lower alkylene group. The lower alkylene and heterocyclyl of a(heteroalicyclyl)alkyl may be substituted or unsubstituted. Examplesinclude but are not limited tetrahydro-2H-pyran-4-yl(methyl),piperidin-4-yl(ethyl), piperidin-4-yl(propyl),tetrahydro-2H-thiopyran-4-yl(methyl) and 1,3-thiazinan-4-yl(methyl).

“Lower alkylene groups” are straight-chained —CH₂— tethering groups,forming bonds to connect molecular fragments via their terminal carbonatoms. Examples include but are not limited to methylene (—CH₂—),ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—) and butylene(—CH₂CH₂CH₂CH₂—). A lower alkylene group can be substituted by replacingone or more hydrogen of the lower alkylene group and/or by substitutingboth hydrogens on the same carbon with a cycloalkyl group

As used herein, the term “hydroxy” refers to a —OH group.

As used herein, “alkoxy” refers to the formula —OR wherein R is analkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl,heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl),heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein. Anon-limiting list of alkoxys are methoxy, ethoxy, n-propoxy,1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy,tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted orunsubstituted.

As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) andheterocyclyl(alkyl) connected, as substituents, via a carbonyl group.Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acylmay be substituted or unsubstituted.

A “cyano” group refers to a “—CN” group.

The term “halogen atom” or “halogen” as used herein, means any one ofthe radio-stable atoms of column 7 of the Periodic Table of theElements, such as, fluorine, chlorine, bromine and iodine.

A “thiocarbonyl” group refers to a “—C(═S)R” group in which R can be thesame as defined with respect to O-carboxy. A thiocarbonyl may besubstituted or unsubstituted.

An “O-carbamyl” group refers to a “—OC(═O)N(R_(A)R_(B))” group in whichR_(A) and R_(B) can be independently hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted.

An “N-carbamyl” group refers to an “ROC(═O)N(R_(A))—” group in which Rand R_(A) can be independently hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An N-carbamyl may be substituted or unsubstituted.

An “O-thiocarbamyl” group refers to a “—OC(═S)—N(R_(A)R_(B))” group inwhich R_(A) and R_(B) can be independently hydrogen, an alkyl, analkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl,heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An O-thiocarbamyl may be substituted orunsubstituted.

An “N-thiocarbamyl” group refers to an “ROC(═S)N(R_(A))—” group in whichR and R_(A) can be independently hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An N-thiocarbamyl may be substituted orunsubstituted.

A “C-amido” group refers to a “—C(═O)N(R_(A)R_(B))” group in which R_(A)and R_(B) can be independently hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). A C-amido may be substituted or unsubstituted.

An “N-amido” group refers to a “RC(═O)N(R_(A))—” group in which R andR_(A) can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, acycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An N-amido may be substituted or unsubstituted.

An “S-sulfonamido” group refers to a “—SO₂N(R_(A)R_(B))” group in whichR_(A) and R_(B) can be independently hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An S-sulfonamido may be substituted orunsubstituted.

An “N-sulfonamido” group refers to a “RSO₂N(R_(A))—” group in which Rand R_(A) can be independently hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An N-sulfonamido may be substituted orunsubstituted.

An “O-carboxy” group refers to a “RC(═O)O—” group in which R can behydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, acycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl),aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as definedherein. An O-carboxy may be substituted or unsubstituted.

The terms “ester” and “C-carboxy” refer to a “—C(═O)OR” group in which Rcan be the same as defined with respect to O-carboxy. An ester andC-carboxy may be substituted or unsubstituted.

An “isocyanato” group refers to a “—NCO” group.

A “thiocyanato” group refers to a “—CNS” group.

An “isothiocyanato” group refers to an “—NCS” group.

A “nitro” group refers to an “—NO₂” group.

A “sulfenyl” group refers to an “—SR” group in which R can be hydrogen,an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl,heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl),heteroaryl(alkyl) or heterocyclyl(alkyl). A sulfenyl may be substitutedor unsubstituted.

A “sulfinyl” group refers to an “—S(═O)—R” group in which R can be thesame as defined with respect to sulfenyl. A sulfinyl may be substitutedor unsubstituted.

A “sulfonyl” group refers to an “SO₂R” group in which R can be the sameas defined with respect to sulfenyl. A sulfonyl may be substituted orunsubstituted.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkyl, di-haloalkyl and tri-haloalkyl). Such groups include butare not limited to, chloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1-chloro-2-fluoromethyl and 2-fluoroisobutyl. Ahaloalkyl may be substituted or unsubstituted.

As used herein, “haloalkoxy” refers to an alkoxy group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). Such groups includebut are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. Ahaloalkoxy may be substituted or unsubstituted.

The term “amino” as used herein refers to a —NH₂ group.

A “mono-substituted amino” group refers to a “—NHR” group in which R canbe an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl,heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl),heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. Amono-substituted amino may be substituted or unsubstituted. Examples ofmono-substituted amino groups include, but are not limited to,—NH(methyl), —NH(phenyl) and the like.

A “di-substituted amino” group refers to a “—NR_(A)R_(B)” group in whichR_(A) and R_(B) can be independently an alkyl, an alkenyl, an alkynyl, acycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl), as defined herein. A di-substituted amino may besubstituted or unsubstituted. Examples of di-substituted amino groupsinclude, but are not limited to, —N(methyl)₂, —N(phenyl)(methyl),—N(ethyl)(methyl) and the like.

Where the numbers of substituents is not specified (e.g. haloalkyl),there may be one or more substituents present. For example “haloalkyl”may include one or more of the same or different halogens. As anotherexample, “C₁-C₃ alkoxyphenyl” may include one or more of the same ordifferent alkoxy groups containing one, two or three atoms.

As used herein, a radical indicates species with a single, unpairedelectron such that the species containing the radical can be covalentlybonded to another species. Hence, in this context, a radical is notnecessarily a free radical. Rather, a radical indicates a specificportion of a larger molecule. The term “radical” can be usedinterchangeably with the term “group.”

The term “pharmaceutically acceptable salt” refers to a salt of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, the salt is an acidaddition salt of the compound. Pharmaceutical salts can be obtained byreacting a compound with inorganic acids such as hydrohalic acid (e.g.,hydrochloric acid or hydrobromic acid), a sulfuric acid, a nitric acidand a phosphoric acid (such as 2,3-dihydroxypropyl dihydrogenphosphate). Pharmaceutical salts can also be obtained by reacting acompound with an organic acid such as aliphatic or aromatic carboxylicor sulfonic acids, for example formic, acetic, succinic, lactic, malic,tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic,p-toluensulfonic, trifluoroacetic, benzoic, salicylic,2-oxopentanedioic, or naphthalenesulfonic acid. Pharmaceutical salts canalso be obtained by reacting a compound with a base to form a salt suchas an ammonium salt, an alkali metal salt, such as a sodium, a potassiumor a lithium salt, an alkaline earth metal salt, such as a calcium or amagnesium salt, a salt of a carbonate, a salt of a bicarbonate, a saltof organic bases such as dicyclohexylamine, N-methyl-D-glucamine,tris(hydroxymethyl)methylamine, C₁-C₇ alkylamine, cyclohexylamine,triethanolamine, ethylenediamine, and salts with amino acids such asarginine and lysine. For compounds of Formulae (I) and/or (II), thoseskilled in the art understand that when a salt is formed by protonationof a nitrogen-based group (for example, NH₂), the nitrogen-based groupcan be associated with a positive charge (for example, NH₂ can becomeNH₃ ⁺) and the positive charge can be balanced by a negatively chargedcounterion (such as Cl⁻).

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, enantiomerically enriched, racemicmixture, diastereomerically pure, diastereomerically enriched, or astereoisomeric mixture. In addition it is understood that, in anycompound described herein having one or more double bond(s) generatinggeometrical isomers that can be defined as E or Z, each double bond mayindependently be E or Z a mixture thereof. Likewise, it is understoodthat, in any compound described, all tautomeric forms are also intendedto be included.

It is to be understood that where compounds disclosed herein haveunfilled valencies, then the valencies are to be filled with hydrogensor isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2(deuterium).

It is understood that the compounds described herein can be labeledisotopically. Substitution with isotopes such as deuterium may affordcertain therapeutic advantages resulting from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements. Each chemical element as represented in a compoundstructure may include any isotope of said element. For example, in acompound structure a hydrogen atom may be explicitly disclosed orunderstood to be present in the compound. At any position of thecompound that a hydrogen atom may be present, the hydrogen atom can beany isotope of hydrogen, including but not limited to hydrogen-1(protium) and hydrogen-2 (deuterium). Thus, reference herein to acompound encompasses all potential isotopic forms unless the contextclearly dictates otherwise.

It is understood that the methods and combinations described hereininclude crystalline forms (also known as polymorphs, which include thedifferent crystal packing arrangements of the same elemental compositionof a compound), amorphous phases, salts, solvates, and hydrates. In someembodiments, the compounds described herein exist in solvated forms withpharmaceutically acceptable solvents such as water, ethanol, or thelike. In other embodiments, the compounds described herein exist inunsolvated form. Solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and may be formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, or the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

Terms and phrases used in this application, and variations thereof,especially in the appended claims, unless otherwise expressly stated,should be construed as open ended as opposed to limiting. As examples ofthe foregoing, the term ‘including’ should be read to mean ‘including,without limitation,’ ‘including but not limited to,’ or the like; theterm ‘comprising’ as used herein is synonymous with ‘including,’‘containing,’ or ‘characterized by,’ and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps; theterm ‘having’ should be interpreted as ‘having at least;’ the term‘includes’ should be interpreted as ‘includes but is not limited to;’the term ‘example’ is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof; and use of termslike ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words ofsimilar meaning should not be understood as implying that certainfeatures are critical, essential, or even important to the structure orfunction, but instead as merely intended to highlight alternative oradditional features that may or may not be utilized in a particularembodiment. In addition, the term “comprising” is to be interpretedsynonymously with the phrases “having at least” or “including at least”.When used in the context of a process, the term “comprising” means thatthe process includes at least the recited steps, but may includeadditional steps. When used in the context of a compound, composition ordevice, the term “comprising” means that the compound, composition ordevice includes at least the recited features or components, but mayalso include additional features or components. Likewise, a group ofitems linked with the conjunction ‘and’ should not be read as requiringthat each and every one of those items be present in the grouping, butrather should be read as ‘and/or’ unless expressly stated otherwise.Similarly, a group of items linked with the conjunction ‘or’ should notbe read as requiring mutual exclusivity among that group, but rathershould be read as ‘and/or’ unless expressly stated otherwise.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity. The indefinite article “a” or “an” does not exclude aplurality. A single processor or other unit may fulfill the functions ofseveral items recited in the claims. The mere fact that certain measuresare recited in mutually different dependent claims does not indicatethat a combination of these measures cannot be used to advantage. Anyreference signs in the claims should not be construed as limiting thescope.

Compounds

Some embodiments disclosed herein relate to a compound of Formula (I),or a pharmaceutically acceptable salt thereof:

wherein: R¹ can be selected from H (hydrogen), D (deuterium), asubstituted or unsubstituted C₁₋₆ alkyl and a substituted orunsubstituted C₁₋₆ haloalkyl; R² can be H (hydrogen) or C(═O)R^(2A);R^(2A) can be selected from H (hydrogen), D (deuterium), a substitutedor unsubstituted C₁₋₃₀ alkyl, a substituted or unsubstituted C₂₋₃₀alkenyl, a substituted or unsubstituted C₂₋₃₀ alkynyl, a substituted orunsubstituted C₃₋₃₀ cycloalkyl, a substituted or unsubstituted C₃₋₃₀cycloalkenyl, a substituted or unsubstituted C₈₋₃₀ cycloalkynyl, asubstituted or unsubstituted C₆₋₃₀ aryl, a substituted or unsubstitutedheteroaryl, a substituted or unsubstituted heterocyclyl, a substitutedor unsubstituted aryl(C₁₋₆ alkyl), a substituted or unsubstitutedheteroaryl(C₁₋₆ alkyl), a substituted or unsubstituted heterocyclyl(C₁₋₆alkyl) and a substituted or unsubstituted C₁₋₈ haloalkyl; R³ can beselected from H (hydrogen), D (deuterium), halo, hydroxy, a substitutedor unsubstituted C₁₋₈ alkyl, a substituted or unsubstituted C₂₋₈alkenyl, a substituted or unsubstituted C₂₋₈ alkynyl, a substituted orunsubstituted C₃₋₂₀ cycloalkyl, a substituted or unsubstituted C₃₋₂₀cycloalkenyl, a substituted or unsubstituted C₈₋₂₀ cycloalkynyl, asubstituted or unsubstituted C₆₋₂₀ aryl, a substituted or unsubstitutedheteroaryl, a substituted or unsubstituted heterocyclyl, a substitutedor unsubstituted aryl(C₁₋₆ alkyl), a substituted or unsubstitutedheteroaryl(C₁₋₆ alkyl), a substituted or unsubstituted heterocyclyl(C₁₋₆alkyl), a substituted or unsubstituted C₁₋₈ haloalkyl and a substitutedor unsubstituted sulfonyl; A¹ can be CR⁴R⁵; R⁴ and R⁵ can beindependently selected from H (hydrogen), D (deuterium), unsubstitutedC₁₋₈ alkyl and an unsubstituted C₁₋₆ haloalkyl, or R⁴ and R⁵ can betaken together to form an optionally substituted C₃₋₆ cycloalkyl; and mcan be 0, 1, 2 or 3.

In some embodiments, R¹ can be H (hydrogen). In other embodiments, R¹can be D (deuterium). In still other embodiments, R¹ can be asubstituted C₁₋₆ alkyl. In yet still other embodiments, R¹ can be anunsubstituted C₁₋₆ alkyl. For example, R¹ can be methyl. Other examplesof C₁₋₆ alkyl groups include ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, tert-butyl, pentyl (straight and branched) and hexyl(straight and branched). In some embodiments, R¹ can be a substitutedC₁₋₆ haloalkyl. In other embodiments, R¹ can be an unsubstituted C₁₋₆haloalkyl. Examples of suitable C₁₋₆ haloalkyls include, but are notlimited to, CF₃, CH₂CF₃, CH₂CHF₂ and CH₂CH₂F.

In some embodiments, R² can be H. When R² is H, NR¹R² of Formula (I) canbe an amino or a mono-substituted amine group that can be attached tothe bicyclopentane ring directly or through an optionally substitutedalkylene group. In some embodiments, R² can be an amino group directlyattached to the bicyclopentane ring. In some embodiments, R² can be anamino group attached to the bicyclopentane ring through an optionallysubstituted methylene. In other embodiments, R² can be an amino groupattached to the bicyclopentane ring through an optionally substitutedethylene. In still other embodiments, R² can be an amino group attachedto the bicyclopentane ring through an optionally substituted propylene.In some embodiments, R² can be a mono-substituted group directlyattached to the bicyclopentane ring. In other embodiments, R² can be amono-substituted group attached to the bicyclopentane ring through anoptionally substituted methylene. In still other embodiments, R² can bea mono-substituted group attached to the bicyclopentane ring through anoptionally substituted ethylene. In yet still other embodiments, R² canbe a mono-substituted group attached to the bicyclopentane ring throughan optionally substituted propylene.

In some embodiments, R² can be C(═O)R^(2A). When R² is C(═O)R^(2A),NR¹R² of Formula (I) can be an optionally substituted N-amido group thatcan be attached to the bicyclopentane ring directly or through anoptionally substituted alkylene group. In some embodiments, R² can be anN-amido group directly attached to the bicyclopentane ring. In otherembodiments, R² can be an N-amido group attached to the bicyclopentanering through an optionally substituted methylene. In still otherembodiments, R² can be an N-amido group attached to the bicyclopentanering through an optionally substituted ethylene. In yet still otherembodiments, R² can be an N-amido group attached to the bicyclopentanering through an optionally substituted propylene. The alkylene group canbe substituted or unsubstituted and can include one or more deuteriums.

When R² is C(═O)R^(2A), R^(2A) can be a variety of groups. In someembodiments, R^(2A) can be H (hydrogen). In other embodiments, R^(2A)can be D (deuterium). In still other embodiments, R^(2A) can be asubstituted C₁₋₃₀ alkyl. In yet still other embodiments, R^(2A) can bean unsubstituted C₁₋₃₀ alkyl. The alkyl group can be a long alkyl having1 to 30 carbons, a medium alkyl having 1 to 12 carbon atoms or a loweralkyl having 1 to 6 carbon atoms. Examples of lower alkyl groupsinclude, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, atert-butyl, pentyl (straight and branched) and hexyl (straight andbranched). In some embodiments, R^(2A) can be an unsubstituted alkylhaving 8 to 26 carbon atoms. Examples of unsubstituted C₁₋₃₀ alkylsinclude, but are not limited to, —(CH₂)₆CH₃, —(CH₂)₈CH₃, —(CH₂)₁₀CH₃,—(CH₂)₁₂CH₃, —(CH₂)₁₄CH₃, —(CH₂)₁₆CH₃, —(CH₂)₁₈CH₃, —(CH₂)₂₀CH₃,—(CH₂)₂₂CH₃ and —(CH₂)₂₄CH₃.

In some embodiments, R^(2A) can be a substituted C₂₋₃₀ alkenyl. In otherembodiments, R^(2A) can be an unsubstituted C₂₋₃₀ alkenyl. In stillother embodiments, R^(2A) can be a substituted C₂₋₃₀ alkynyl. In yetstill other embodiments, R^(2A) can be an unsubstituted C₂₋₃₀ alkynyl.Similar to alkyls, alkenyls and alkynyls can be a long alkenyl and/oralkynyl having 2 to 30 carbons, a medium alkenyl and/or alkynyl having 2to 12 carbon atoms or a lower alkenyl and/or alkynyl having 2 to 6carbon atoms. In some embodiments, R^(2A) can be an unsubstitutedalkenyl having 14 to 22 carbon atoms. Examples of unsubstituted C₂₋₃₀alkenyls include, but are not limited to, —(CH₂)₇CH═CH(CH₂)₃CH₃,—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃, —(CH₂)₇CH═CH(CH₂) CH₃,(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃, —(CH₂)₇CH═CH(CH₂)₇CH₃,(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃, —(CH₂)₉CH═CH(CH₂) CH₃,—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃, —(CH₂)₁₁CH═CH(CH₂)₇CH₃,—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃, (CH₂)₄CH═CHCH(CH₃)₂and (CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃.

In some embodiments, R^(2A) can be the aliphatic tail of a saturated oran unsaturated fatty acid. As an example, R^(2A) can be the aliphatictail of caprylic acid (HOOC(CH₂)₆CH₃). In this example of caprylic acid,the aliphatic tail is bolded and italicized. When the saturated or anunsaturated fatty acid becomes part of a compound of Formula (I), thecarbon of the carboxylic acid of the saturated or an unsaturated fattyacid becomes the carbon that is bold and underlined carbon ofC(═O)R^(2A). For example, when R^(2A) is the aliphatic tail of caprylicacid, the compound of Formula (I) can have the following structure:

A non-limiting list of suitable saturated or an unsaturated fatty acidsare myristoleic acid, palmitoleic, sapienic acid, linoleic acid, oleicacid, linoleiaidic acid, elaidic acid, alpha-linolenic acid, vaccenicacid, arachidonic acid, erucic acid, eicosapentaenoic acid,(E)-8-methylnon-6-enoic acid, docosahexaenoic acid, caprylic acid,capric acid, lauric acid, myristic acid, palmitic acid, stearic acid,arachidic acid, behenic acid, lignoceric acid and cerotic acid.

Cyclic groups can also be present at R^(2A). In some embodiments, R^(2A)can be a substituted C₃₋₃₀ cycloalkyl. In other embodiments, R^(2A) canbe an unsubstituted C₃₋₃₀ cycloalkyl. In still other embodiments, R^(2A)can be a substituted C₃₋₃₀ cycloalkenyl. In yet still other embodiments,R^(2A) can be an unsubstituted C₃₋₃₀ cycloalkenyl. In some embodiments,R^(2A) can be a substituted C₈₋₃₀ cycloalkynyl. In some embodiments,R^(2A) can be an unsubstituted C₈₋₃₀ cycloalkynyl. The number of carbonring atoms of a cycloalkyl and a cycloalkenyl can vary. In someembodiments, the number of carbon ring atoms of a cycloalkyl and acycloalkenyl can be 3 to 30, 3 to 20, 3 to 10, 3 to 8 or 3 to 6.Likewise, the number of carbon ring atoms of a cycloalkynyl can vary,for example, 8 to 30, 8 to 20 or 8 to 10. The number rings of acycloalkyl, a cycloalkenyl and a cycloalkynyl can also vary. In someembodiments, a cycloalkyl, a cycloalkenyl and/or a cycloalkynyl can bemono-cyclic.

In other embodiments, a cycloalkyl, a cycloalkenyl and a cycloalkynylcan be bi-cyclic or tri-cyclic. As described herein, the rings of amulti-cyclic cycloalkyl, cycloalkenyl and cycloalkynyl can be joinedtogether to form fused ring system, a bridged ring system and/orspiro-connected ring system.

In some embodiments, R^(2A) can be a substituted C₆₋₃₀ aryl. In otherembodiments, R^(2A) can be an unsubstituted C₆₋₃₀ aryl. Examples ofsuitable C₆₋₃₀ aryl groups include, but are not limited to phenyl,naphthyl, anthracenyl and phenanthrene. When R^(2A) is a substitutedphenyl, the phenyl ring can be substituted at the ortho, meta and/orpara position(s). As described herein, the number of substituent groupspresent on a substituted aryl group can vary from 1, 2, 3, to 3 or moresubstituent groups.

Cyclic groups of R^(2A) can also contain one or more heteroatoms. Forexample, in some embodiments, R^(2A) can be a substituted heteroaryl. Inother embodiments, R^(2A) can be an unsubstituted heteroaryl. In someembodiments, R^(2A) can be a substituted or unsubstituted mono-cyclicheteroaryl. In some embodiments, R^(2A) can be a substituted orunsubstituted multi-cyclic heteroaryl, for example, a substituted orunsubstituted bi-cyclic heteroaryl.

In some embodiments, R^(2A) can be a substituted heterocyclyl. In otherembodiments, R^(2A) can be an unsubstituted heterocyclyl. In someembodiments, R^(2A) can be a substituted or unsubstituted mono-cyclicheterocyclyl. In some embodiments, R^(2A) can be a substituted orunsubstituted multi-cyclic heterocyclyl (such as a bi-cyclicheterocyclyl). A mono-cyclic heteroaryl and/or a mono-cyclicheterocyclyl can include 5 to 6 ring atoms, and a bi-cyclic heteroaryland/or a bi-cyclic heterocyclyl can include 9 to 10 ring atoms.

A cyclic group connected via a carbon-based linker can be present as aR^(2A) group. In some embodiments, R^(2A) can be a substituted aryl(C₁₋₆alkyl). In other embodiments, R^(2A) can be an unsubstituted aryl(C₁₋₆alkyl). As an example, R^(2A) can be a substituted or unsubstitutedbenzyl. In some embodiments, R^(2A) can be a substituted heteroaryl(C₁₋₆alkyl). In other embodiments, R^(2A) can be an unsubstitutedheteroaryl(C₁₋₆ alkyl). In some embodiments, R^(2A) can be a substitutedor unsubstituted mono-cyclic heteroaryl(C₁₋₆ alkyl). In someembodiments, R^(2A) can be a substituted or unsubstituted multi-cyclicheteroaryl(C₁₋₆ alkyl), such as a substituted or unsubstituted bi-cyclicheteroaryl(C₁₋₆ alkyl). In some embodiments, R^(2A) can be a substitutedheterocyclyl(C₁₋₆ alkyl). In other embodiments, R^(2A) can be anunsubstituted heterocyclyl(C₁₋₆ alkyl). In some embodiments, R^(2A) canbe a substituted or unsubstituted mono-cyclic heterocyclyl(C₁₋₆ alkyl).In some embodiments, R^(2A) can be a substituted or unsubstitutedmulti-cyclic heterocyclyl(C₁₋₆ alkyl), for example, a substituted orunsubstituted bi-cyclic heterocyclyl(C₁₋₆ alkyl).

In some embodiments, R^(2A) can be a substituted C₁₋₈ haloalkyl. Inother embodiments, R^(2A) can be an unsubstituted C₁₋₈ haloalkyl.Examples of suitable C₁₋₈ haloalkyls include, but are not limited to,CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂ and CH₂CH₂F.

Various groups can also be present for R³. In some embodiments, R³ canbe H (hydrogen). In other embodiments, R³ can be D (deuterium). In stillother embodiments, R³ can be a halo. For example, R³ can be F (fluoro)or Cl (chloro). In yet still other embodiments, R³ can be hydroxy.

In some embodiments, R³ can be a substituted C₁₋₈ alkyl. Various groupscan be present on a substituted C₁₋₈ alkyl of R³, such as a hydroxygroup. In other embodiments, R³ can be an unsubstituted C₁₋₈ alkyl.Suitable substituted and unsubstituted C₁₋₈ alkyl groups include,methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl,pentyl (straight and branched), hexyl (straight and branched), heptyl(straight and branched) and octyl (straight and branched). In someembodiments, R³ can be —C(CH₃)₂OH.

In some embodiments, R³ can be a substituted C₂₋₈ alkenyl. In otherembodiments, R³ can be an unsubstituted C₂₋₈ alkenyl. In someembodiments, R³ can be a substituted C₂₋₄ alkenyl. In other embodiments,R³ can be an unsubstituted C₂₋₄ alkenyl. In some embodiments, R³ can bea substituted C₂₋₈ alkynyl. In other embodiments, R³ can be anunsubstituted C₂₋₈ alkynyl. In some embodiments, R³ can be a substitutedC₂₋₄ alkynyl. In other embodiments, R³ can be an unsubstituted C₂₋₄alkynyl.

As with R^(2A), R³ can be a substituted or an unsubstituted cyclicgroup. In some embodiments, R³ can be a substituted C₃₋₂₀ cycloalkyl. Insome embodiments, R³ can be an unsubstituted C₃₋₄ cycloalkyl. In otherembodiments, R³ can be an unsubstituted C₃₋₂₀ cycloalkyl. The cycloalkylgroup can be a mono-cyclic cycloalkyl or a multi-cyclic cycloalkyl group(such as a bi-cyclic cycloalkyl). In some embodiments, R³ can be asubstituted C₃₋₂₀ cycloalkenyl. In other embodiments, R³ can be anunsubstituted C₃₋₂₀ cycloalkenyl. Similar to a cycloalkyl group, acycloalkenyl group can be a mono-cyclic cycloalkenyl or a multi-cycliccycloalkenyl group (such as a bi-cyclic cycloalkenyl). In someembodiments, R³ can be a substituted C₃₋₂₀ cycloalkynyl. In otherembodiments, R³ can be an unsubstituted C₃₋₂₀ cycloalkynyl. Acycloalkynyl can be mono-cyclic, bi-cyclic and/or tri-cyclic. Asdescribed herein, when the cycloalkyl, cycloalkenyl and/or cycloalkynylgroup includes more than 1 ring, the rings can be joined together in afused, spiro or bridged fashion. In some embodiments, a cycloalkyland/or a cycloalkenyl can include 3 to 10 ring carbon atom(s). In otherembodiments, a cycloalkyl and/or a cycloalkenyl can include 3 to 6 ringcarbon atom(s).

Other examples of suitable cyclic groups include aryl, heteroaryl andheterocyclyl groups. In some embodiments, R³ can be a substituted C₆₋₂₀aryl. In other embodiments, R³ can be an unsubstituted C₆₋₂₀ aryl.Examples of C₆₋₃₀ aryl groups are described herein. In some embodiments,R³ can be an unsubstituted phenyl. In other embodiments, R³ can be asubstituted phenyl. The phenyl ring can be substituted with 1substituent group, 2 substituents groups or 3 or more substituents. Thesubstituent group(s) can be present at the ortho, meta and/or paraposition(s). In some embodiments, R³ can be a substituted naphthyl. Inother embodiments, R³ can be an unsubstituted naphthyl.

In some embodiments, R³ can be a substituted heteroaryl. In otherembodiments, R³ can be an unsubstituted heteroaryl. The number of ringsof a heteroaryl group can vary. For example, in some embodiments, R³ canbe a substituted mono-cyclic heteroaryl. In other embodiments, R³ can bean unsubstituted mono-cyclic heteroaryl. The mono-cyclic heteroaryl caninclude 5 or 6 ring atoms. In still other embodiments, R³ can be asubstituted multi-cyclic heteroaryl (for example, a substitutedbi-cyclic heteroaryl). In yet still other embodiments, R³ can be anunsubstituted multi-cyclic heteroaryl (for example, an unsubstitutedbi-cyclic heteroaryl). The number of ring atoms of a multi-cyclicheteroaryl can vary. For example, a multi-cyclic heteroaryl can include9 or 10 ring atoms.

In some embodiments, R³ can be a substituted heterocyclyl. In otherembodiments, R³ can be an unsubstituted heterocyclyl. As with aheteroaryl group, the number of rings of a heterocyclyl group can vary.In some embodiments, R³ can be a substituted mono-cyclic heterocyclyl.In other embodiments, R³ can be an unsubstituted mono-cyclicheterocyclyl. In still other embodiments, R³ can be a substitutedbi-cyclic heterocyclyl. In yet still other embodiments, R³ can be anunsubstituted bi-cyclic heterocyclyl. A mono-cyclic heterocyclyl and abi-cyclic heterocyclyl can include a various number of ring atoms. Amono-cyclic heterocyclyl can include 5 to 6 ring atoms, and a bi-cyclicheterocyclyl can include 9 to 10 ring atoms.

As described herein, a linker can be used to connect a cyclic group tothe bicyclopentane. In some embodiments, R³ can be a substitutedaryl(C₁₋₆ alkyl). In other embodiments, R³ can be an unsubstitutedaryl(C₁₋₆ alkyl). For example, in some embodiments, R³ can be asubstituted or unsubstituted benzyl. The phenyl ring of a benzyl groupcan be substituted with 1 substituent, 2 substituents, 3 substituents or3 or more substituents.

In some embodiments, R³ can be a substituted heteroaryl(C₁₋₆ alkyl). Inother embodiments, R³ can be an unsubstituted heteroaryl(C₁₋₆ alkyl).The heteroaryl ring can be a substituted or unsubstituted mono-cyclicheteroaryl or a substituted or unsubstituted multi-cyclic heteroaryl(such as a bi-cyclic heteroaryl). In still other embodiments, R³ can bea substituted heterocyclyl(C₁₋₆ alkyl). In other embodiments, R³ can bean unsubstituted heterocyclyl(C₁₋₆ alkyl). The number of rings of theheterocyclyl or a heterocyclyl(C₁₋₆ alkyl) can vary. For example, insome embodiments, R³ can be a substituted mono-cyclic heterocyclyl(C₁₋₆alkyl). In other embodiments, R³ can be an unsubstituted mono-cyclicheterocyclyl(C₁₋₆ alkyl). In still other embodiments, R³ can be asubstituted multi-cyclic heterocyclyl(C₁₋₆ alkyl), for example, asubstituted bi-cyclic heterocyclyl(C₁₋₆ alkyl). In yet still otherembodiments, R³ can be an unsubstituted multi-cyclic heterocyclyl(C₁₋₆alkyl), for example, an unsubstituted bi-cyclic heterocyclyl(C₁₋₆alkyl). As described herein, the number of ring atoms of aheteroaryl(C₁₋₆ alkyl) and/or a heterocyclyl(C₁₋₆ alkyl) can also vary.In some embodiments, a heteroaryl(C₁₋₆ alkyl) and/or a heterocyclyl(C₁₋₆alkyl) can include 5 or 6 ring atoms. In other embodiments, aheteroaryl(C₁₋₆ alkyl) and/or a heterocyclyl(C₁₋₆ alkyl) can include 9or 10 ring atoms.

In some embodiments, R³ can be a substituted C₁₋₈ haloalkyl. In otherembodiments, R³ can be an unsubstituted C₁₋₈ haloalkyl. For example, R³can be a substituted or an unsubstituted C₁₋₄ haloalkyl. In someembodiments, R³ can be CF₃. In other embodiments, R³ can be CHF₂. Instill other embodiments, R³ can be CH₂F. In yet still other embodiments,R³ can be CF₂CH₃.

In some embodiments, R³ can be a substituted sulfonyl. In otherembodiments, R³ can be an unsubstituted sulfonyl. In some embodiments,R³ can be SO₂R⁺⁺, wherein R⁺⁺ can be hydrogen, an optionally substitutedC₁₋₆ alkyl, an optionally substituted C₂₋₆ alkenyl, an optionallysubstituted C₃₋₆ cycloalkyl, an optionally substituted mono-cyclic aryl,an optionally substituted mono-cyclic heteroaryl or an optionallysubstituted mono-cyclic heterocyclyl. In other embodiments, R³ can beSO₂R⁺⁺, wherein R⁺⁺ can be an unsubstituted C₁₋₆ alkyl, an unsubstitutedC₂₋₆ alkenyl or an unsubstituted C₃₋₆ cycloalkyl. In some embodiments,R³ can be SO₂CH₃.

A compound of Formula (I) can include a linker group between thebicyclopentane ring and NR¹R² or the NR¹R² group can be connecteddirectly to the bicyclopentane ring. In some embodiments, m can be 0. Inother embodiments, m can be 1. In still other embodiments, m can be 2.In yet still other embodiments, m can be 3.

In some embodiments, the linker group can be represented by A¹, whereinA¹ can be CR⁴R⁵. In some embodiments, R⁴ can be H. In other embodiments,R⁴ can be D. In still other embodiments, R⁴ can be an unsubstituted C₁₋₈alkyl. In some embodiments, R⁴ can be an unsubstituted C₁₋₆ haloalkyl,such as CF₃, CHF₂ or CH₂F. In some embodiments, R⁵ can be H. In otherembodiments, R⁵ can be D. In other embodiments, R⁵ can be anunsubstituted C₁₋₈ alkyl. In some embodiments, R⁵ can be anunsubstituted C₁₋₆ haloalkyl, such as CF₃, CHF₂ or CH₂F. In someembodiments, R⁴ and R⁵ can be taken together to form an optionallysubstituted C₃₋₆ cycloalkyl. In some embodiments, one of R⁴ and R⁵ canbe H, and the other of R⁴ and R⁵ can be an unsubstituted C₁₋₈ alkyl oran unsubstituted C₁₋₆ haloalkyl. In other embodiments, R⁴ and R⁵ can beindependently an unsubstituted C₁₋₈ alkyl or an unsubstituted C₁₋₆haloalkyl. In some embodiments, at least one of R⁴ and R⁵ can be D.

In some embodiments, R⁴ and R⁵ both can be H.

In some embodiments, R³ can be H, F, Cl, an unsubstituted C₁₋₄ alkyl, ahydroxy substituted C₁₋₄ alkyl, an unsubstituted C₁₋₄ haloalkyl, anunsubstituted C₃₋₆ cycloalkyl or SO₂CH₃, R¹ can be H or CH₃, and R² canbe H. In some embodiments, R³ can be H, F, Cl, an unsubstituted C₁₋₄alkyl, a hydroxy substituted C₁₋₄ alkyl, an unsubstituted C₁₋₄haloalkyl, an unsubstituted C₃₋₆ cycloalkyl or SO₂CH₃, R¹ can be H orCH₃, and R² can be C(═O)R^(2A). In some embodiments, R³ can be H, F, Cl,an unsubstituted C₁₋₄ alkyl, a hydroxy substituted C₁₋₄ alkyl, anunsubstituted C₁₋₄ haloalkyl, an unsubstituted C₃₋₆ cycloalkyl orSO₂CH₃, R¹ can be H or CH₃, and R² can be C(═O)R^(2A), wherein R^(2A)can be an unsubstituted C₁₋₄ alkyl or an unsubstituted C₂₋₄ alkenyl. Insome embodiments, R³ can be H, F, Cl, an unsubstituted C₁₋₄ alkyl, ahydroxy substituted C₁₋₄ alkyl, an unsubstituted C₁₋₄ haloalkyl, anunsubstituted C₃₋₆ cycloalkyl or SO₂CH₃, R¹ can be H or CH₃, and R² canbe C(═O)R^(2A), wherein R^(2A) can be an unsubstituted C₈₋₃₀ alkyl or anunsubstituted C₈₋₃₀ alkenyl.

As described herein, the number of substituent groups present on asubstituted R¹, R^(2A), R³, R⁴ and/or R⁵ group can vary from 1, 2, 3, to3 or more substituents groups. When more than 1 substituent group ispresent, a group can be the same as at least one other group.Additionally and/or in the alternative, when more than 1 substituentgroup is present, a group can be different from at least one othergroup.

A non-limiting list of examples of compounds of Formula (I), or apharmaceutically acceptable salt, include:

or a pharmaceutically acceptable salt of any of the foregoing.

Additional examples of compounds of Formula (I), or a pharmaceuticallyacceptable salt, include the following:

or a pharmaceutically acceptable salt of any of the foregoing.

Further examples of compounds of Formula (I), or a pharmaceuticallyacceptable salt, include the following:

or a pharmaceutically acceptable salt of the foregoing.

Further examples of compounds of Formula (I), or a pharmaceuticallyacceptable salt, are provided in Table 1.

TABLE 1

R¹ R² R^(2A) R³ m H C(═O)R^(2A) —(CH₂)₆CH₃ H 0 H C(═O)R^(2A) —(CH₂)₈CH₃H 0 H C(═O)R^(2A) —(CH₂)₁₀CH₃ H 0 H C(═O)R^(2A) —(CH₂)₁₂CH₃ H 0 HC(═O)R^(2A) —(CH₂)₁₄CH₃ H 0 H C(═O)R^(2A) —(CH₂)₁₆CH₃ H 0 H C(═O)R^(2A)—(CH₂)₁₈CH₃ H 0 H C(═O)R^(2A) —(CH₂)₂₀CH₃ H 0 H C(═O)R^(2A) —(CH₂)₂₂CH₃H 0 H C(═O)R^(2A) —(CH₂)₂₄CH₃ H 0 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ H0 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ H 0 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ H 0 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ H0 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃ H 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ H 0 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ H 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ H 0 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ H 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ H 0 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ H 0 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ H 0 HC(═O)R^(2A) —(CH₂)₆CH₃ CH₃ 0 H C(═O)R^(2A) —(CH₂)₈CH₃ CH₃ 0 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CH₃ 0 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CH₃ 0 HC(═O)R^(2A) —(CH₂)₁₄CH₃ CH₃ 0 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CH₃ 0 HC(═O)R^(2A) —(CH₂)₁₈CH₃ CH₃ 0 H C(═O)R^(2A) —(CH₂)₂₀CH₃ CH₃ 0 HC(═O)R^(2A) —(CH₂)₂₂CH₃ CH₃ 0 H C(═O)R^(2A) —(CH₂)₂₄CH₃ CH₃ 0 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CH₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CH₃ 0 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃CH₃ 0 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CH₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CH₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH₃ 0 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CH₃ 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CH₃ 0 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CH₃ 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH₃ 0 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ CH₃ 0 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH₃ 0 HC(═O)R^(2A) —(CH₂)₆CH₃ CH(CH₃)₂ 0 H C(═O)R^(2A) —(CH₂)₈CH₃ CH(CH₃)₂ 0 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CH(CH₃)₂ 0 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CH(CH₃)₂ 0H C(═O)R^(2A) —(CH₂)₁₄CH₃ CH(CH₃)₂ 0 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CH(CH₃)₂0 H C(═O)R^(2A) —(CH₂)₁₈CH₃ CH(CH₃)₂ 0 H C(═O)R^(2A) —(CH₂)₂₀CH₃CH(CH₃)₂ 0 H C(═O)R^(2A) —(CH₂)₂₂CH₃ CH(CH₃)₂ 0 H C(═O)R^(2A)—(CH₂)₂₄CH₃ CH(CH₃)₂ 0 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CH(CH₃)₂ 0 HC(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CH(CH₃)₂ 0 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CH(CH₃)₂ 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CH(CH₃)₂ 0 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CH(CH₃)₂ 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH(CH₃)₂ 0 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CH(CH₃)₂ 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CH(CH₃)₂ 0 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CH(CH₃)₂ 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH(CH₃)₂ 0 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ CH(CH₃)₂ 0 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH(CH₃)₂ 0 HC(═O)R^(2A) —(CH₂)₆CH₃ C(CH₃)₃ 0 H C(═O)R^(2A) —(CH₂)₈CH₃ C(CH₃)₃ 0 HC(═O)R^(2A) —(CH₂)₁₀CH₃ C(CH₃)₃ 0 H C(═O)R^(2A) —(CH₂)₁₂CH₃ C(CH₃)₃ 0 HC(═O)R^(2A) —(CH₂)₁₄CH₃ C(CH₃)₃ 0 H C(═O)R^(2A) —(CH₂)₁₆CH₃ C(CH₃)₃ 0 HC(═O)R^(2A) —(CH₂)₁₈CH₃ C(CH₃)₃ 0 H C(═O)R^(2A) —(CH₂)₂₀CH₃ C(CH₃)₃ 0 HC(═O)R^(2A) —(CH₂)₂₂CH₃ C(CH₃)₃ 0 H C(═O)R^(2A) —(CH₂)₂₄CH₃ C(CH₃)₃ 0 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ C(CH₃)₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ C(CH₃)₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ C(CH₃)₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₃ 0 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ C(CH₃)₃ 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₃ 0 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ C(CH₃)₃ 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₃ 0 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ C(CH₃)₃ 0 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₃ 0 HC(═O)R^(2A) —(CH₂)₆CH₃ cyclopropyl 0 H C(═O)R^(2A) —(CH₂)₈CH₃cyclopropyl 0 H C(═O)R^(2A) —(CH₂)₁₀CH₃ cyclopropyl 0 H C(═O)R^(2A)—(CH₂)₁₂CH₃ cyclopropyl 0 H C(═O)R^(2A) —(CH₂)₁₄CH₃ cyclopropyl 0 HC(═O)R^(2A) —(CH₂)₁₆CH₃ cyclopropyl 0 H C(═O)R^(2A) —(CH₂)₁₈CH₃cyclopropyl 0 H C(═O)R^(2A) —(CH₂)₂₀CH₃ cyclopropyl 0 H C(═O)R^(2A)—(CH₂)₂₂CH₃ cyclopropyl 0 H C(═O)R^(2A) —(CH₂)₂₄CH₃ cyclopropyl 0 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ cyclopropyl 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ cyclopropyl 0 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ cyclopropyl 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ cyclopropyl 0 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ cyclopropyl 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ cyclopropyl 0 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ cyclopropyl 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ cyclopropyl 0 HC(═O)R^(2A) —(CH₂)₁₁CH═CH(CH₂)₇CH₃ cyclopropyl 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ cyclopropyl 0 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ cyclopropyl 0 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ cyclopropyl 0H C(═O)R^(2A) —(CH₂)₆CH₃ Cl 0 H C(═O)R^(2A) —(CH₂)₈CH₃ Cl 0 HC(═O)R^(2A) —(CH₂)₁₀CH₃ Cl 0 H C(═O)R^(2A) —(CH₂)₁₂CH₃ Cl 0 HC(═O)R^(2A) —(CH₂)₁₄CH₃ Cl 0 H C(═O)R^(2A) —(CH₂)₁₆CH₃ Cl 0 HC(═O)R^(2A) —(CH₂)₁₈CH₃ Cl 0 H C(═O)R^(2A) —(CH₂)₂₀CH₃ Cl 0 HC(═O)R^(2A) —(CH₂)₂₂CH₃ Cl 0 H C(═O)R^(2A) —(CH₂)₂₄CH₃ Cl 0 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ Cl 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ Cl 0 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃Cl 0 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ Cl 0 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ Cl 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ Cl 0 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ Cl 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ Cl 0 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ Cl 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ Cl 0 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ Cl 0 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ Cl 0 HC(═O)R^(2A) —(CH₂)₆CH₃ F 0 H C(═O)R^(2A) —(CH₂)₈CH₃ F 0 H C(═O)R^(2A)—(CH₂)₁₀CH₃ F 0 H C(═O)R^(2A) —(CH₂)₁₂CH₃ F 0 H C(═O)R^(2A) —(CH₂)₁₄CH₃F 0 H C(═O)R^(2A) —(CH₂)₁₆CH₃ F 0 H C(═O)R^(2A) —(CH₂)₁₈CH₃ F 0 HC(═O)R^(2A) —(CH₂)₂₀CH₃ F 0 H C(═O)R^(2A) —(CH₂)₂₂CH₃ F 0 H C(═O)R^(2A)—(CH₂)₂₄CH₃ F 0 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ F 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ F 0 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃ F0 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ F 0 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ F 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ F 0 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ F 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ F 0 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ F 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ F 0 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ F 0 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ F 0 HC(═O)R^(2A) —(CH₂)₆CH₃ S(O)₂CH₃ 0 H C(═O)R^(2A) —(CH₂)₈CH₃ S(O)₂CH₃ 0 HC(═O)R^(2A) —(CH₂)₁₀CH₃ S(O)₂CH₃ 0 H C(═O)R^(2A) —(CH₂)₁₂CH₃ S(O)₂CH₃ 0H C(═O)R^(2A) —(CH₂)₁₄CH₃ S(O)₂CH₃ 0 H C(═O)R^(2A) —(CH₂)₁₆CH₃ S(O)₂CH₃0 H C(═O)R^(2A) —(CH₂)₁₈CH₃ S(O)₂CH₃ 0 H C(═O)R^(2A) —(CH₂)₂₀CH₃S(O)₂CH₃ 0 H C(═O)R^(2A) —(CH₂)₂₂CH₃ S(O)₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₂₄CH₃ S(O)₂CH₃ 0 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ S(O)₂CH₃ 0 HC(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ S(O)₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ S(O)₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ S(O)₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ S(O)₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ S(O)₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ S(O)₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ S(O)₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ S(O)₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ S(O)₂CH₃ 0 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ S(O)₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ S(O)₂CH₃ 0 HC(═O)R^(2A) —(CH₂)₆CH₃ CF₃ 0 H C(═O)R^(2A) —(CH₂)₈CH₃ CF₃ 0 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CF₃ 0 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CF₃ 0 HC(═O)R^(2A) —(CH₂)₁₄CH₃ CF₃ 0 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CF₃ 0 HC(═O)R^(2A) —(CH₂)₁₈CH₃ CF₃ 0 H C(═O)R^(2A) —(CH₂)₂₀CH₃ CF₃ 0 HC(═O)R^(2A) —(CH₂)₂₂CH₃ CF₃ 0 H C(═O)R^(2A) —(CH₂)₂₄CH₃ CF₃ 0 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CF₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₃ 0 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃CF₃ 0 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CF₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₃ 0 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CF₃ 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₃ 0 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CF₃ 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₃ 0 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ CF₃ 0 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₃ 0 HC(═O)R^(2A) —(CH₂)₆CH₃ CHF₂ 0 H C(═O)R^(2A) —(CH₂)₈CH₃ CHF₂ 0 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CHF₂ 0 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CHF₂ 0 HC(═O)R^(2A) —(CH₂)₁₄CH₃ CHF₂ 0 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CHF₂ 0 HC(═O)R^(2A) —(CH₂)₁₈CH₃ CHF₂ 0 H C(═O)R^(2A) —(CH₂)₂₀CH₃ CHF₂ 0 HC(═O)R^(2A) —(CH₂)₂₂CH₃ CHF₂ 0 H C(═O)R^(2A) —(CH₂)₂₄CH₃ CHF₂ 0 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CHF₂ 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CHF₂ 0 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃CHF₂ 0 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CHF₂ 0 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CHF₂ 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CHF₂ 0 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CHF₂ 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CHF₂ 0 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CHF₂ 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CHF₂ 0 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ CHF₂ 0 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CHF₂ 0 HC(═O)R^(2A) —(CH₂)₆CH₃ CF₂CH₃ 0 H C(═O)R^(2A) —(CH₂)₈CH₃ CF₂CH₃ 0 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CF₂CH₃ 0 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CF₂CH₃ 0 HC(═O)R^(2A) —(CH₂)₁₄CH₃ CF₂CH₃ 0 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CF₂CH₃ 0 HC(═O)R^(2A) —(CH₂)₁₈CH₃ CF₂CH₃ 0 H C(═O)R^(2A) —(CH₂)₂₀CH₃ CF₂CH₃ 0 HC(═O)R^(2A) —(CH₂)₂₂CH₃ CF₂CH₃ 0 H C(═O)R^(2A) —(CH₂)₂₄CH₃ CF₂CH₃ 0 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CF₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CF₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CF₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CF₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CF₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₂CH₃ 0 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ CF₂CH₃ 0 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₂CH₃ 0 HC(═O)R^(2A) —(CH₂)₆CH₃ C(CH₃)₂OH 0 H C(═O)R^(2A) —(CH₂)₈CH₃ C(CH₃)₂OH 0H C(═O)R^(2A) —(CH₂)₁₀CH₃ C(CH₃)₂OH 0 H C(═O)R^(2A) —(CH₂)₁₂CH₃C(CH₃)₂OH 0 H C(═O)R^(2A) —(CH₂)₁₄CH₃ C(CH₃)₂OH 0 H C(═O)R^(2A)—(CH₂)₁₆CH₃ C(CH₃)₂OH 0 H C(═O)R^(2A) —(CH₂)₁₈CH₃ C(CH₃)₂OH 0 HC(═O)R^(2A) —(CH₂)₂₀CH₃ C(CH₃)₂OH 0 H C(═O)R^(2A) —(CH₂)₂₂CH₃ C(CH₃)₂OH0 H C(═O)R^(2A) —(CH₂)₂₄CH₃ C(CH₃)₂OH 0 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₃CH₃ C(CH₃)₂OH 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₂OH 0 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ C(CH₃)₂OH 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₂OH 0 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ C(CH₃)₂OH 0 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₂OH 0 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ C(CH₃)₂OH 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₂OH 0 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ C(CH₃)₂OH 0 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₂OH 0 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ C(CH₃)₂OH 0 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₂OH 0 HC(═O)R^(2A) —(CH₂)₆CH₃ H 1 H C(═O)R^(2A) —(CH₂)₈CH₃ H 1 H C(═O)R^(2A)—(CH₂)₁₀CH₃ H 1 H C(═O)R^(2A) —(CH₂)₁₂CH₃ H 1 H C(═O)R^(2A) —(CH₂)₁₄CH₃H 1 H C(═O)R^(2A) —(CH₂)₁₆CH₃ H 1 H C(═O)R^(2A) —(CH₂)₁₈CH₃ H 1 HC(═O)R^(2A) —(CH₂)₂₀CH₃ H 1 H C(═O)R^(2A) —(CH₂)₂₂CH₃ H 1 H C(═O)R^(2A)—(CH₂)₂₄CH₃ H 1 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ H 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ H 1 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃ H1 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ H 1 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ H 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ H 1 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ H 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ H 1 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ H 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ H 1 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ H 1 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ H 1 HC(═O)R^(2A) —(CH₂)₆CH₃ CH₃ 1 H C(═O)R^(2A) —(CH₂)₈CH₃ CH₃ 1 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CH₃ 1 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CH₃ 1 HC(═O)R^(2A) —(CH₂)₁₄CH₃ CH₃ 1 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CH₃ 1 HC(═O)R^(2A) —(CH₂)₁₈CH₃ CH₃ 1 H C(═O)R^(2A) —(CH₂)₂₀CH₃ CH₃ 1 HC(═O)R^(2A) —(CH₂)₂₂CH₃ CH₃ 1 H C(═O)R^(2A) —(CH₂)₂₄CH₃ CH₃ 1 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CH₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CH₃ 1 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃CH₃ 1 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CH₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CH₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH₃ 1 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CH₃ 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CH₃ 1 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CH₃ 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH₃ 1 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ CH₃ 1 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH₃ 1 HC(═O)R^(2A) —(CH₂)₆CH₃ CH(CH₃)₂ 1 H C(═O)R^(2A) —(CH₂)₈CH₃ CH(CH₃)₂ 1 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CH(CH₃)₂ 1 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CH(CH₃)₂ 1H C(═O)R^(2A) —(CH₂)₁₄CH₃ CH(CH₃)₂ 1 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CH(CH₃)₂1 H C(═O)R^(2A) —(CH₂)₁₈CH₃ CH(CH₃)₂ 1 H C(═O)R^(2A) —(CH₂)₂₀CH₃CH(CH₃)₂ 1 H C(═O)R^(2A) —(CH₂)₂₂CH₃ CH(CH₃)₂ 1 H C(═O)R^(2A)—(CH₂)₂₄CH₃ CH(CH₃)₂ 1 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CH(CH₃)₂ 1 HC(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CH(CH₃)₂ 1 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CH(CH₃)₂ 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CH(CH₃)₂ 1 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CH(CH₃)₂ 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH(CH₃)₂ 1 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CH(CH₃)₂ 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CH(CH₃)₂ 1 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CH(CH₃)₂ 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH(CH₃)₂ 1 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ CH(CH₃)₂ 1 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH(CH₃)₂ 1 HC(═O)R^(2A) —(CH₂)₆CH₃ C(CH₃)₃ 1 H C(═O)R^(2A) —(CH₂)₈CH₃ C(CH₃)₃ 1 HC(═O)R^(2A) —(CH₂)₁₀CH₃ C(CH₃)₃ 1 H C(═O)R^(2A) —(CH₂)₁₂CH₃ C(CH₃)₃ 1 HC(═O)R^(2A) —(CH₂)₁₄CH₃ C(CH₃)₃ 1 H C(═O)R^(2A) —(CH₂)₁₆CH₃ C(CH₃)₃ 1 HC(═O)R^(2A) —(CH₂)₁₈CH₃ C(CH₃)₃ 1 H C(═O)R^(2A) —(CH₂)₂₀CH₃ C(CH₃)₃ 1 HC(═O)R^(2A) —(CH₂)₂₂CH₃ C(CH₃)₃ 1 H C(═O)R^(2A) —(CH₂)₂₄CH₃ C(CH₃)₃ 1 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ C(CH₃)₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ C(CH₃)₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ C(CH₃)₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₃ 1 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ C(CH₃)₃ 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₃ 1 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ C(CH₃)₃ 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₃ 1 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ C(CH₃)₃ 1 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₃ 1 HC(═O)R^(2A) —(CH₂)₆CH₃ cyclopropyl 1 H C(═O)R^(2A) —(CH₂)₈CH₃cyclopropyl 1 H C(═O)R^(2A) —(CH₂)₁₀CH₃ cyclopropyl 1 H C(═O)R^(2A)—(CH₂)₁₂CH₃ cyclopropyl 1 H C(═O)R^(2A) —(CH₂)₁₄CH₃ cyclopropyl 1 HC(═O)R^(2A) —(CH₂)₁₆CH₃ cyclopropyl 1 H C(═O)R^(2A) —(CH₂)₁₈CH₃cyclopropyl 1 H C(═O)R^(2A) —(CH₂)₂₀CH₃ cyclopropyl 1 H C(═O)R^(2A)—(CH₂)₂₂CH₃ cyclopropyl 1 H C(═O)R^(2A) —(CH₂)₂₄CH₃ cyclopropyl 1 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ cyclopropyl 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ cyclopropyl 1 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ cyclopropyl 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ cyclopropyl 1 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ cyclopropyl 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ cyclopropyl 1 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ cyclopropyl 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ cyclopropyl 1 HC(═O)R^(2A) —(CH₂)₁₁CH═CH(CH₂)₇CH₃ cyclopropyl 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ cyclopropyl 1 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ cyclopropyl 1 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ cyclopropyl 1H C(═O)R^(2A) —(CH₂)₆CH₃ Cl 1 H C(═O)R^(2A) —(CH₂)₈CH₃ Cl 1 HC(═O)R^(2A) —(CH₂)₁₀CH₃ Cl 1 H C(═O)R^(2A) —(CH₂)₁₂CH₃ Cl 1 HC(═O)R^(2A) —(CH₂)₁₄CH₃ Cl 1 H C(═O)R^(2A) —(CH₂)₁₆CH₃ Cl 1 HC(═O)R^(2A) —(CH₂)₁₈CH₃ Cl 1 H C(═O)R^(2A) —(CH₂)₂₀CH₃ Cl 1 HC(═O)R^(2A) —(CH₂)₂₂CH₃ Cl 1 H C(═O)R^(2A) —(CH₂)₂₄CH₃ Cl 1 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ Cl 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ Cl 1 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃Cl 1 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ Cl 1 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ Cl 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ Cl 1 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ Cl 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ Cl 1 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ Cl 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ Cl 1 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ Cl 1 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ Cl 1 HC(═O)R^(2A) —(CH₂)₆CH₃ F 1 H C(═O)R^(2A) —(CH₂)₈CH₃ F 1 H C(═O)R^(2A)—(CH₂)₁₀CH₃ F 1 H C(═O)R^(2A) —(CH₂)₁₂CH₃ F 1 H C(═O)R^(2A) —(CH₂)₁₄CH₃F 1 H C(═O)R^(2A) —(CH₂)₁₆CH₃ F 1 H C(═O)R^(2A) —(CH₂)₁₈CH₃ F 1 HC(═O)R^(2A) —(CH₂)₂₀CH₃ F 1 H C(═O)R^(2A) —(CH₂)₂₂CH₃ F 1 H C(═O)R^(2A)—(CH₂)₂₄CH₃ F 1 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ F 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ F 1 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃ F1 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ F 1 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ F 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ F 1 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ F 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ F 1 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ F 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ F 1 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ F 1 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ F 1 HC(═O)R^(2A) —(CH₂)₆CH₃ S(O)₂CH₃ 1 H C(═O)R^(2A) —(CH₂)₈CH₃ S(O)₂CH₃ 1 HC(═O)R^(2A) —(CH₂)₁₀CH₃ S(O)₂CH₃ 1 H C(═O)R^(2A) —(CH₂)₁₂CH₃ S(O)₂CH₃ 1H C(═O)R^(2A) —(CH₂)₁₄CH₃ S(O)₂CH₃ 1 H C(═O)R^(2A) —(CH₂)₁₆CH₃ S(O)₂CH₃1 H C(═O)R^(2A) —(CH₂)₁₈CH₃ S(O)₂CH₃ 1 H C(═O)R^(2A) —(CH₂)₂₀CH₃S(O)₂CH₃ 1 H C(═O)R^(2A) —(CH₂)₂₂CH₃ S(O)₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₂₄CH₃ S(O)₂CH₃ 1 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ S(O)₂CH₃ 1 HC(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ S(O)₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ S(O)₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ S(O)₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ S(O)₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ S(O)₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ S(O)₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ S(O)₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ S(O)₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ S(O)₂CH₃ 1 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ S(O)₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ S(O)₂CH₃ 1 HC(═O)R^(2A) —(CH₂)₆CH₃ CF₃ 1 H C(═O)R^(2A) —(CH₂)₈CH₃ CF₃ 1 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CF₃ 1 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CF₃ 1 HC(═O)R^(2A) —(CH₂)₁₄CH₃ CF₃ 1 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CF₃ 1 HC(═O)R^(2A) —(CH₂)₁₈CH₃ CF₃ 1 H C(═O)R^(2A) —(CH₂)₂₀CH₃ CF₃ 1 HC(═O)R^(2A) —(CH₂)₂₂CH₃ CF₃ 1 H C(═O)R^(2A) —(CH₂)₂₄CH₃ CF₃ 1 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CF₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₃ 1 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃CF₃ 1 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CF₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₃ 1 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CF₃ 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₃ 1 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CF₃ 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₃ 1 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ CF₃ 1 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₃ 1 HC(═O)R^(2A) —(CH₂)₆CH₃ CHF₂ 1 H C(═O)R^(2A) —(CH₂)₈CH₃ CHF₂ 1 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CHF₂ 1 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CHF₂ 1 HC(═O)R^(2A) —(CH₂)₁₄CH₃ CHF₂ 1 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CHF₂ 1 HC(═O)R^(2A) —(CH₂)₁₈CH₃ CHF₂ 1 H C(═O)R^(2A) —(CH₂)₂₀CH₃ CHF₂ 1 HC(═O)R^(2A) —(CH₂)₂₂CH₃ CHF₂ 1 H C(═O)R^(2A) —(CH₂)₂₄CH₃ CHF₂ 1 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CHF₂ 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CHF₂ 1 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃CHF₂ 1 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CHF₂ 1 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CHF₂ 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CHF₂ 1 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CHF₂ 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CHF₂ 1 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CHF₂ 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CHF₂ 1 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ CHF₂ 1 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CHF₂ 1 HC(═O)R^(2A) —(CH₂)₆CH₃ CF₂CH₃ 1 H C(═O)R^(2A) —(CH₂)₈CH₃ CF₂CH₃ 1 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CF₂CH₃ 1 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CF₂CH₃ 1 HC(═O)R^(2A) —(CH₂)₁₄CH₃ CF₂CH₃ 1 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CF₂CH₃ 1 HC(═O)R^(2A) —(CH₂)₁₈CH₃ CF₂CH₃ 1 H C(═O)R^(2A) —(CH₂)₂₀CH₃ CF₂CH₃ 1 HC(═O)R^(2A) —(CH₂)₂₂CH₃ CF₂CH₃ 1 H C(═O)R^(2A) —(CH₂)₂₄CH₃ CF₂CH₃ 1 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CF₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CF₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CF₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CF₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CF₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₂CH₃ 1 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ CF₂CH₃ 1 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₂CH₃ 1 HC(═O)R^(2A) —(CH₂)₆CH₃ C(CH₃)₂OH 1 H C(═O)R^(2A) —(CH₂)₈CH₃ C(CH₃)₂OH 1H C(═O)R^(2A) —(CH₂)₁₀CH₃ C(CH₃)₂OH 1 H C(═O)R^(2A) —(CH₂)₁₂CH₃C(CH₃)₂OH 1 H C(═O)R^(2A) —(CH₂)₁₄CH₃ C(CH₃)₂OH 1 H C(═O)R^(2A)—(CH₂)₁₆CH₃ C(CH₃)₂OH 1 H C(═O)R^(2A) —(CH₂)₁₈CH₃ C(CH₃)₂OH 1 HC(═O)R^(2A) —(CH₂)₂₀CH₃ C(CH₃)₂OH 1 H C(═O)R^(2A) —(CH₂)₂₂CH₃ C(CH₃)₂OH1 H C(═O)R^(2A) —(CH₂)₂₄CH₃ C(CH₃)₂OH 1 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₃CH₃ C(CH₃)₂OH 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₂OH 1 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ C(CH₃)₂OH 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₂OH 1 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ C(CH₃)₂OH 1 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₂OH 1 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ C(CH₃)₂OH 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₂OH 1 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ C(CH₃)₂OH 1 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₂OH 1 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ C(CH₃)₂OH 1 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₂OH 1 HC(═O)R^(2A) —(CH₂)₆CH₃ H 2 H C(═O)R^(2A) —(CH₂)₈CH₃ H 2 H C(═O)R^(2A)—(CH₂)₁₀CH₃ H 2 H C(═O)R^(2A) —(CH₂)₁₂CH₃ H 2 H C(═O)R^(2A) —(CH₂)₁₄CH₃H 2 H C(═O)R^(2A) —(CH₂)₁₆CH₃ H 2 H C(═O)R^(2A) —(CH₂)₁₈CH₃ H 2 HC(═O)R^(2A) —(CH₂)₂₀CH₃ H 2 H C(═O)R^(2A) —(CH₂)₂₂CH₃ H 2 H C(═O)R^(2A)—(CH₂)₂₄CH₃ H 2 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ H 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ H 2 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃ H2 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ H 2 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ H 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ H 2 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ H 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ H 2 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ H 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ H 2 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ H 2 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ H 2 HC(═O)R^(2A) —(CH₂)₆CH₃ CH₃ 2 H C(═O)R^(2A) —(CH₂)₈CH₃ CH₃ 2 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CH₃ 2 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CH₃ 2 HC(═O)R^(2A) —(CH₂)₁₄CH₃ CH₃ 2 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CH₃ 2 HC(═O)R^(2A) —(CH₂)₁₈CH₃ CH₃ 2 H C(═O)R^(2A) —(CH₂)₂₀CH₃ CH₃ 2 HC(═O)R^(2A) —(CH₂)₂₂CH₃ CH₃ 2 H C(═O)R^(2A) —(CH₂)₂₄CH₃ CH₃ 2 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CH₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CH₃ 2 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃CH₃ 2 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CH₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CH₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH₃ 2 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CH₃ 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CH₃ 2 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CH₃ 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH₃ 2 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ CH₃ 2 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH₃ 2 HC(═O)R^(2A) —(CH₂)₆CH₃ CH(CH₃)₂ 2 H C(═O)R^(2A) —(CH₂)₈CH₃ CH(CH₃)₂ 2 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CH(CH₃)₂ 2 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CH(CH₃)₂ 2H C(═O)R^(2A) —(CH₂)₁₄CH₃ CH(CH₃)₂ 2 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CH(CH₃)₂2 H C(═O)R^(2A) —(CH₂)₁₈CH₃ CH(CH₃)₂ 2 H C(═O)R^(2A) —(CH₂)₂₀CH₃CH(CH₃)₂ 2 H C(═O)R^(2A) —(CH₂)₂₂CH₃ CH(CH₃)₂ 2 H C(═O)R^(2A)—(CH₂)₂₄CH₃ CH(CH₃)₂ 2 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CH(CH₃)₂ 2 HC(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CH(CH₃)₂ 2 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CH(CH₃)₂ 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CH(CH₃)₂ 2 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CH(CH₃)₂ 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH(CH₃)₂ 2 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CH(CH₃)₂ 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CH(CH₃)₂ 2 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CH(CH₃)₂ 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH(CH₃)₂ 2 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ CH(CH₃)₂ 2 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH(CH₃)₂ 2 HC(═O)R^(2A) —(CH₂)₆CH₃ C(CH₃)₃ 2 H C(═O)R^(2A) —(CH₂)₈CH₃ C(CH₃)₃ 2 HC(═O)R^(2A) —(CH₂)₁₀CH₃ C(CH₃)₃ 2 H C(═O)R^(2A) —(CH₂)₁₂CH₃ C(CH₃)₃ 2 HC(═O)R^(2A) —(CH₂)₁₄CH₃ C(CH₃)₃ 2 H C(═O)R^(2A) —(CH₂)₁₆CH₃ C(CH₃)₃ 2 HC(═O)R^(2A) —(CH₂)₁₈CH₃ C(CH₃)₃ 2 H C(═O)R^(2A) —(CH₂)₂₀CH₃ C(CH₃)₃ 2 HC(═O)R^(2A) —(CH₂)₂₂CH₃ C(CH₃)₃ 2 H C(═O)R^(2A) —(CH₂)₂₄CH₃ C(CH₃)₃ 2 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ C(CH₃)₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ C(CH₃)₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ C(CH₃)₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₃ 2 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ C(CH₃)₃ 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₃ 2 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ C(CH₃)₃ 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₃ 2 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ C(CH₃)₃ 2 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₃ 2 HC(═O)R^(2A) —(CH₂)₆CH₃ cyclopropyl 2 H C(═O)R^(2A) —(CH₂)₈CH₃cyclopropyl 2 H C(═O)R^(2A) —(CH₂)₁₀CH₃ cyclopropyl 2 H C(═O)R^(2A)—(CH₂)₁₂CH₃ cyclopropyl 2 H C(═O)R^(2A) —(CH₂)₁₄CH₃ cyclopropyl 2 HC(═O)R^(2A) —(CH₂)₁₆CH₃ cyclopropyl 2 H C(═O)R^(2A) —(CH₂)₁₈CH₃cyclopropyl 2 H C(═O)R^(2A) —(CH₂)₂₀CH₃ cyclopropyl 2 H C(═O)R^(2A)—(CH₂)₂₂CH₃ cyclopropyl 2 H C(═O)R^(2A) —(CH₂)₂₄CH₃ cyclopropyl 2 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ cyclopropyl 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ cyclopropyl 2 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ cyclopropyl 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ cyclopropyl 2 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ cyclopropyl 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ cyclopropyl 2 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ cyclopropyl 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ cyclopropyl 2 HC(═O)R^(2A) —(CH₂)₁₁CH═CH(CH₂)₇CH₃ cyclopropyl 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ cyclopropyl 2 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ cyclopropyl 2 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ cyclopropyl 2H C(═O)R^(2A) —(CH₂)₆CH₃ Cl 2 H C(═O)R^(2A) —(CH₂)₈CH₃ Cl 2 HC(═O)R^(2A) —(CH₂)₁₀CH₃ Cl 2 H C(═O)R^(2A) —(CH₂)₁₂CH₃ Cl 2 HC(═O)R^(2A) —(CH₂)₁₄CH₃ Cl 2 H C(═O)R^(2A) —(CH₂)₁₆CH₃ Cl 2 HC(═O)R^(2A) —(CH₂)₁₈CH₃ Cl 2 H C(═O)R^(2A) —(CH₂)₂₀CH₃ Cl 2 HC(═O)R^(2A) —(CH₂)₂₂CH₃ Cl 2 H C(═O)R^(2A) —(CH₂)₂₄CH₃ Cl 2 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ Cl 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ Cl 2 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃Cl 2 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ Cl 2 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ Cl 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ Cl 2 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ Cl 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ Cl 2 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ Cl 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ Cl 2 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ Cl 2 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ Cl 2 HC(═O)R^(2A) —(CH₂)₆CH₃ F 2 H C(═O)R^(2A) —(CH₂)₈CH₃ F 2 H C(═O)R^(2A)—(CH₂)₁₀CH₃ F 2 H C(═O)R^(2A) —(CH₂)₁₂CH₃ F 2 H C(═O)R^(2A) —(CH₂)₁₄CH₃F 2 H C(═O)R^(2A) —(CH₂)₁₆CH₃ F 2 H C(═O)R^(2A) —(CH₂)₁₈CH₃ F 2 HC(═O)R^(2A) —(CH₂)₂₀CH₃ F 2 H C(═O)R^(2A) —(CH₂)₂₂CH₃ F 2 H C(═O)R^(2A)—(CH₂)₂₄CH₃ F 2 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ F 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ F 2 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃ F2 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ F 2 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ F 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ F 2 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ F 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ F 2 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ F 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ F 2 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ F 2 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ F 2 HC(═O)R^(2A) —(CH₂)₆CH₃ S(O)₂CH₃ 2 H C(═O)R^(2A) —(CH₂)₈CH₃ S(O)₂CH₃ 2 HC(═O)R^(2A) —(CH₂)₁₀CH₃ S(O)₂CH₃ 2 H C(═O)R^(2A) —(CH₂)₁₂CH₃ S(O)₂CH₃ 2H C(═O)R^(2A) —(CH₂)₁₄CH₃ S(O)₂CH₃ 2 H C(═O)R^(2A) —(CH₂)₁₆CH₃ S(O)₂CH₃2 H C(═O)R^(2A) —(CH₂)₁₈CH₃ S(O)₂CH₃ 2 H C(═O)R^(2A) —(CH₂)₂₀CH₃S(O)₂CH₃ 2 H C(═O)R^(2A) —(CH₂)₂₂CH₃ S(O)₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₂₄CH₃ S(O)₂CH₃ 2 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ S(O)₂CH₃ 2 HC(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ S(O)₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ S(O)₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ S(O)₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ S(O)₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ S(O)₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ S(O)₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ S(O)₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ S(O)₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ S(O)₂CH₃ 2 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ S(O)₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ S(O)₂CH₃ 2 HC(═O)R^(2A) —(CH₂)₆CH₃ CF₃ 2 H C(═O)R^(2A) —(CH₂)₈CH₃ CF₃ 2 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CF₃ 2 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CF₃ 2 HC(═O)R^(2A) —(CH₂)₁₄CH₃ CF₃ 2 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CF₃ 2 HC(═O)R^(2A) —(CH₂)₁₈CH₃ CF₃ 2 H C(═O)R^(2A) —(CH₂)₂₀CH₃ CF₃ 2 HC(═O)R^(2A) —(CH₂)₂₂CH₃ CF₃ 2 H C(═O)R^(2A) —(CH₂)₂₄CH₃ CF₃ 2 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CF₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₃ 2 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃CF₃ 2 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CF₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₃ 2 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CF₃ 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₃ 2 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CF₃ 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₃ 2 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ CF₃ 2 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₃ 2 HC(═O)R^(2A) —(CH₂)₆CH₃ CHF₂ 2 H C(═O)R^(2A) —(CH₂)₈CH₃ CHF₂ 2 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CHF₂ 2 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CHF₂ 2 HC(═O)R^(2A) —(CH₂)₁₄CH₃ CHF₂ 2 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CHF₂ 2 HC(═O)R^(2A) —(CH₂)₁₈CH₃ CHF₂ 2 H C(═O)R^(2A) —(CH₂)₂₀CH₃ CHF₂ 2 HC(═O)R^(2A) —(CH₂)₂₂CH₃ CHF₂ 2 H C(═O)R^(2A) —(CH₂)₂₄CH₃ CHF₂ 2 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CHF₂ 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CHF₂ 2 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃CHF₂ 2 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CHF₂ 2 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CHF₂ 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CHF₂ 2 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CHF₂ 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CHF₂ 2 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CHF₂ 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CHF₂ 2 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ CHF₂ 2 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CHF₂ 2 HC(═O)R^(2A) —(CH₂)₆CH₃ CF₂CH₃ 2 H C(═O)R^(2A) —(CH₂)₈CH₃ CF₂CH₃ 2 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CF₂CH₃ 2 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CF₂CH₃ 2 HC(═O)R^(2A) —(CH₂)₁₄CH₃ CF₂CH₃ 2 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CF₂CH₃ 2 HC(═O)R^(2A) —(CH₂)₁₈CH₃ CF₂CH₃ 2 H C(═O)R^(2A) —(CH₂)₂₀CH₃ CF₂CH₃ 2 HC(═O)R^(2A) —(CH₂)₂₂CH₃ CF₂CH₃ 2 H C(═O)R^(2A) —(CH₂)₂₄CH₃ CF₂CH₃ 2 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CF₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CF₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CF₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CF₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CF₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₂CH₃ 2 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ CF₂CH₃ 2 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₂CH₃ 2 HC(═O)R^(2A) —(CH₂)₆CH₃ C(CH₃)₂OH 2 H C(═O)R^(2A) —(CH₂)₈CH₃ C(CH₃)₂OH 2H C(═O)R^(2A) —(CH₂)₁₀CH₃ C(CH₃)₂OH 2 H C(═O)R^(2A) —(CH₂)₁₂CH₃C(CH₃)₂OH 2 H C(═O)R^(2A) —(CH₂)₁₄CH₃ C(CH₃)₂OH 2 H C(═O)R^(2A)—(CH₂)₁₆CH₃ C(CH₃)₂OH 2 H C(═O)R^(2A) —(CH₂)₁₈CH₃ C(CH₃)₂OH 2 HC(═O)R^(2A) —(CH₂)₂₀CH₃ C(CH₃)₂OH 2 H C(═O)R^(2A) —(CH₂)₂₂CH₃ C(CH₃)₂OH2 H C(═O)R^(2A) —(CH₂)₂₄CH₃ C(CH₃)₂OH 2 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₃CH₃ C(CH₃)₂OH 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₂OH 2 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ C(CH₃)₂OH 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₂OH 2 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ C(CH₃)₂OH 2 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₂OH 2 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ C(CH₃)₂OH 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₂OH 2 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ C(CH₃)₂OH 2 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₂OH 2 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ C(CH₃)₂OH 2 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₂OH 2 HC(═O)R^(2A) —(CH₂)₆CH₃ H 3 H C(═O)R^(2A) —(CH₂)₈CH₃ H 3 H C(═O)R^(2A)—(CH₂)₁₀CH₃ H 3 H C(═O)R^(2A) —(CH₂)₁₂CH₃ H 3 H C(═O)R^(2A) —(CH₂)₁₄CH₃H 3 H C(═O)R^(2A) —(CH₂)₁₆CH₃ H 3 H C(═O)R^(2A) —(CH₂)₁₈CH₃ H 3 HC(═O)R^(2A) —(CH₂)₂₀CH₃ H 3 H C(═O)R^(2A) —(CH₂)₂₂CH₃ H 3 H C(═O)R^(2A)—(CH₂)₂₄CH₃ H 3 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ H 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ H 3 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃ H3 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ H 3 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ H 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ H 3 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ H 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ H 3 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ H 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ H 3 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ H 3 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ H 3 HC(═O)R^(2A) —(CH₂)₆CH₃ CH₃ 3 H C(═O)R^(2A) —(CH₂)₈CH₃ CH₃ 3 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CH₃ 3 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CH₃ 3 HC(═O)R^(2A) —(CH₂)₁₄CH₃ CH₃ 3 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CH₃ 3 HC(═O)R^(2A) —(CH₂)₁₈CH₃ CH₃ 3 H C(═O)R^(2A) —(CH₂)₂₀CH₃ CH₃ 3 HC(═O)R^(2A) —(CH₂)₂₂CH₃ CH₃ 3 H C(═O)R^(2A) —(CH₂)₂₄CH₃ CH₃ 3 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CH₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CH₃ 3 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃CH₃ 3 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CH₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CH₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH₃ 3 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CH₃ 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CH₃ 3 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CH₃ 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH₃ 3 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ CH₃ 3 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH₃ 3 HC(═O)R^(2A) —(CH₂)₆CH₃ CH(CH₃)₂ 3 H C(═O)R^(2A) —(CH₂)₈CH₃ CH(CH₃)₂ 3 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CH(CH₃)₂ 3 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CH(CH₃)₂ 3H C(═O)R^(2A) —(CH₂)₁₄CH₃ CH(CH₃)₂ 3 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CH(CH₃)₂3 H C(═O)R^(2A) —(CH₂)₁₈CH₃ CH(CH₃)₂ 3 H C(═O)R^(2A) —(CH₂)₂₀CH₃CH(CH₃)₂ 3 H C(═O)R^(2A) —(CH₂)₂₂CH₃ CH(CH₃)₂ 3 H C(═O)R^(2A)—(CH₂)₂₄CH₃ CH(CH₃)₂ 3 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CH(CH₃)₂ 3 HC(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CH(CH₃)₂ 3 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CH(CH₃)₂ 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CH(CH₃)₂ 3 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CH(CH₃)₂ 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH(CH₃)₂ 3 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CH(CH₃)₂ 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CH(CH₃)₂ 3 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CH(CH₃)₂ 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH(CH₃)₂ 3 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ CH(CH₃)₂ 3 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CH(CH₃)₂ 3 HC(═O)R^(2A) —(CH₂)₆CH₃ C(CH₃)₃ 3 H C(═O)R^(2A) —(CH₂)₈CH₃ C(CH₃)₃ 3 HC(═O)R^(2A) —(CH₂)₁₀CH₃ C(CH₃)₃ 3 H C(═O)R^(2A) —(CH₂)₁₂CH₃ C(CH₃)₃ 3 HC(═O)R^(2A) —(CH₂)₁₄CH₃ C(CH₃)₃ 3 H C(═O)R^(2A) —(CH₂)₁₆CH₃ C(CH₃)₃ 3 HC(═O)R^(2A) —(CH₂)₁₈CH₃ C(CH₃)₃ 3 H C(═O)R^(2A) —(CH₂)₂₀CH₃ C(CH₃)₃ 3 HC(═O)R^(2A) —(CH₂)₂₂CH₃ C(CH₃)₃ 3 H C(═O)R^(2A) —(CH₂)₂₄CH₃ C(CH₃)₃ 3 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ C(CH₃)₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ C(CH₃)₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ C(CH₃)₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₃ 3 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ C(CH₃)₃ 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₃ 3 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ C(CH₃)₃ 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₃ 3 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ C(CH₃)₃ 3 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₃ 3 HC(═O)R^(2A) —(CH₂)₆CH₃ cyclopropyl 3 H C(═O)R^(2A) —(CH₂)₈CH₃cyclopropyl 3 H C(═O)R^(2A) —(CH₂)₁₀CH₃ cyclopropyl 3 H C(═O)R^(2A)—(CH₂)₁₂CH₃ cyclopropyl 3 H C(═O)R^(2A) —(CH₂)₁₄CH₃ cyclopropyl 3 HC(═O)R^(2A) —(CH₂)₁₆CH₃ cyclopropyl 3 H C(═O)R^(2A) —(CH₂)₁₈CH₃cyclopropyl 3 H C(═O)R^(2A) —(CH₂)₂₀CH₃ cyclopropyl 3 H C(═O)R^(2A)—(CH₂)₂₂CH₃ cyclopropyl 3 H C(═O)R^(2A) —(CH₂)₂₄CH₃ cyclopropyl 3 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ cyclopropyl 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ cyclopropyl 3 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ cyclopropyl 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ cyclopropyl 3 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ cyclopropyl 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ cyclopropyl 3 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ cyclopropyl 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ cyclopropyl 3 HC(═O)R^(2A) —(CH₂)₁₁CH═CH(CH₂)₇CH₃ cyclopropyl 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ cyclopropyl 3 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ cyclopropyl 3 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ cyclopropyl 3H C(═O)R^(2A) —(CH₂)₆CH₃ Cl 3 H C(═O)R^(2A) —(CH₂)₈CH₃ Cl 3 HC(═O)R^(2A) —(CH₂)₁₀CH₃ Cl 3 H C(═O)R^(2A) —(CH₂)₁₂CH₃ Cl 3 HC(═O)R^(2A) —(CH₂)₁₄CH₃ Cl 3 H C(═O)R^(2A) —(CH₂)₁₆CH₃ Cl 3 HC(═O)R^(2A) —(CH₂)₁₈CH₃ Cl 3 H C(═O)R^(2A) —(CH₂)₂₀CH₃ Cl 3 HC(═O)R^(2A) —(CH₂)₂₂CH₃ Cl 3 H C(═O)R^(2A) —(CH₂)₂₄CH₃ Cl 3 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ Cl 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ Cl 3 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃Cl 3 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ Cl 3 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ Cl 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ Cl 3 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ Cl 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ Cl 3 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ Cl 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ Cl 3 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ Cl 3 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ Cl 3 HC(═O)R^(2A) —(CH₂)₆CH₃ F 3 H C(═O)R^(2A) —(CH₂)₈CH₃ F 3 H C(═O)R^(2A)—(CH₂)₁₀CH₃ F 3 H C(═O)R^(2A) —(CH₂)₁₂CH₃ F 3 H C(═O)R^(2A) —(CH₂)₁₄CH₃F 3 H C(═O)R^(2A) —(CH₂)₁₆CH₃ F 3 H C(═O)R^(2A) —(CH₂)₁₈CH₃ F 3 HC(═O)R^(2A) —(CH₂)₂₀CH₃ F 3 H C(═O)R^(2A) —(CH₂)₂₂CH₃ F 3 H C(═O)R^(2A)—(CH₂)₂₄CH₃ F 3 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ F 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ F 3 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃ F3 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ F 3 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ F 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ F 3 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ F 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ F 3 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ F 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ F 3 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ F 3 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ F 3 HC(═O)R^(2A) —(CH₂)₆CH₃ S(O)₂CH₃ 3 H C(═O)R^(2A) —(CH₂)₈CH₃ S(O)₂CH₃ 3 HC(═O)R^(2A) —(CH₂)₁₀CH₃ S(O)₂CH₃ 3 H C(═O)R^(2A) —(CH₂)₁₂CH₃ S(O)₂CH₃ 3H C(═O)R^(2A) —(CH₂)₁₄CH₃ S(O)₂CH₃ 3 H C(═O)R^(2A) —(CH₂)₁₆CH₃ S(O)₂CH₃3 H C(═O)R^(2A) —(CH₂)₁₈CH₃ S(O)₂CH₃ 3 H C(═O)R^(2A) —(CH₂)₂₀CH₃S(O)₂CH₃ 3 H C(═O)R^(2A) —(CH₂)₂₂CH₃ S(O)₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₂₄CH₃ S(O)₂CH₃ 3 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ S(O)₂CH₃ 3 HC(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ S(O)₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ S(O)₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ S(O)₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ S(O)₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ S(O)₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ S(O)₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ S(O)₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ S(O)₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ S(O)₂CH₃ 3 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ S(O)₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ S(O)₂CH₃ 3 HC(═O)R^(2A) —(CH₂)₆CH₃ CF₃ 3 H C(═O)R^(2A) —(CH₂)₈CH₃ CF₃ 3 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CF₃ 3 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CF₃ 3 HC(═O)R^(2A) —(CH₂)₁₄CH₃ CF₃ 3 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CF₃ 3 HC(═O)R^(2A) —(CH₂)₁₈CH₃ CF₃ 3 H C(═O)R^(2A) —(CH₂)₂₀CH₃ CF₃ 3 HC(═O)R^(2A) —(CH₂)₂₂CH₃ CF₃ 3 H C(═O)R^(2A) —(CH₂)₂₄CH₃ CF₃ 3 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CF₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₃ 3 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃CF₃ 3 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CF₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₃ 3 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CF₃ 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₃ 3 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CF₃ 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₃ 3 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ CF₃ 3 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₃ 3 HC(═O)R^(2A) —(CH₂)₆CH₃ CHF₂ 3 H C(═O)R^(2A) —(CH₂)₈CH₃ CHF₂ 3 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CHF₂ 3 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CHF₂ 3 HC(═O)R^(2A) —(CH₂)₁₄CH₃ CHF₂ 3 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CHF₂ 3 HC(═O)R^(2A) —(CH₂)₁₈CH₃ CHF₂ 3 H C(═O)R^(2A) —(CH₂)₂₀CH₃ CHF₂ 3 HC(═O)R^(2A) —(CH₂)₂₂CH₃ CHF₂ 3 H C(═O)R^(2A) —(CH₂)₂₄CH₃ CHF₂ 3 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CHF₂ 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CHF₂ 3 H C(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₇CH₃CHF₂ 3 H C(═O)R^(2A) —(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CHF₂ 3 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CHF₂ 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CHF₂ 3 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CHF₂ 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CHF₂ 3 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CHF₂ 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CHF₂ 3 H C(═O)R^(2A)—(CH₂)₄CH═CHCH(CH₃)₂ CHF₂ 3 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CHF₂ 3 HC(═O)R^(2A) —(CH₂)₆CH₃ CF₂CH₃ 3 H C(═O)R^(2A) —(CH₂)₈CH₃ CF₂CH₃ 3 HC(═O)R^(2A) —(CH₂)₁₀CH₃ CF₂CH₃ 3 H C(═O)R^(2A) —(CH₂)₁₂CH₃ CF₂CH₃ 3 HC(═O)R^(2A) —(CH₂)₁₄CH₃ CF₂CH₃ 3 H C(═O)R^(2A) —(CH₂)₁₆CH₃ CF₂CH₃ 3 HC(═O)R^(2A) —(CH₂)₁₈CH₃ CF₂CH₃ 3 H C(═O)R^(2A) —(CH₂)₂₀CH₃ CF₂CH₃ 3 HC(═O)R^(2A) —(CH₂)₂₂CH₃ CF₂CH₃ 3 H C(═O)R^(2A) —(CH₂)₂₄CH₃ CF₂CH₃ 3 HC(═O)R^(2A) —(CH₂)₇CH═CH(CH₂)₃CH₃ CF₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CF₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ CF₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ CF₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ CF₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ CF₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₂CH₃ 3 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ CF₂CH₃ 3 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ CF₂CH₃ 3 HC(═O)R^(2A) —(CH₂)₆CH₃ C(CH₃)₂OH 3 H C(═O)R^(2A) —(CH₂)₈CH₃ C(CH₃)₂OH 3H C(═O)R^(2A) —(CH₂)₁₀CH₃ C(CH₃)₂OH 3 H C(═O)R^(2A) —(CH₂)₁₂CH₃C(CH₃)₂OH 3 H C(═O)R^(2A) —(CH₂)₁₄CH₃ C(CH₃)₂OH 3 H C(═O)R^(2A)—(CH₂)₁₆CH₃ C(CH₃)₂OH 3 H C(═O)R^(2A) —(CH₂)₁₈CH₃ C(CH₃)₂OH 3 HC(═O)R^(2A) —(CH₂)₂₀CH₃ C(CH₃)₂OH 3 H C(═O)R^(2A) —(CH₂)₂₂CH₃ C(CH₃)₂OH3 H C(═O)R^(2A) —(CH₂)₂₄CH₃ C(CH₃)₂OH 3 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₃CH₃ C(CH₃)₂OH 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₂OH 3 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ C(CH₃)₂OH 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₂OH 3 H C(═O)R^(2A)—(CH₂)₇CH═CH(CH₂)₇CH₃ C(CH₃)₂OH 3 H C(═O)R^(2A)—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₂OH 3 H C(═O)R^(2A)—(CH₂)₉CH═CH(CH₂)₅CH₃ C(CH₃)₂OH 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃ C(CH₃)₂OH 3 H C(═O)R^(2A)—(CH₂)₁₁CH═CH(CH₂)₇CH₃ C(CH₃)₂OH 3 H C(═O)R^(2A)—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₂OH 3 HC(═O)R^(2A) —(CH₂)₄CH═CHCH(CH₃)₂ C(CH₃)₂OH 3 H C(═O)R^(2A)—(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃ C(CH₃)₂OH 3

In some embodiments, when m is 0, then R² is H. In some embodiments,when m is 0, R¹ and R² are each H, then R³ may not be t-butyl. In someembodiments, a compound of Formula (I), or a pharmaceutically saltthereof may not be.

In some embodiments, when m is 0, R¹ is H, and R² is H, then R³ may notbe selected from H, CH₃, F, I, hydroxy, unsubstituted phenyl, anoptionally substituted bicyclo[1.1.1]pentane and CF₃. In someembodiments, when m is 0, R¹ is CH₃, and R² is H, then R³ may not behydroxy. In some embodiments, a compound of Formula (I) cannot beN,N-diethyl-alpha-methyl-bicyclo[1.1.1]pentane-1-methanamine, or apharmaceutically acceptable salt thereof. In some embodiments, when m is0 and R¹ is H, then R² may not be H. In some embodiments, when m is 1,A¹ is CH₂, R³ is H and R² is hydrogen, then R¹ may not be hydrogen.

In some embodiments, R¹ cannot be H. In other embodiments, R¹ cannot beD. In still other embodiments, R¹ cannot be a substituted C₁₋₆ alkyl. Inyet still other embodiments, R¹ cannot be an unsubstituted C₁₋₆ alkyl.In some embodiments, R¹ cannot be a substituted C₁₋₆ haloalkyl. In otherembodiments, R¹ cannot be an unsubstituted C₁₋₆ haloalkyl.

In some embodiments, R² cannot be H. In some embodiments, R² cannot bean amino group directly attached to the bicyclopentane ring. In otherembodiments, R² cannot be an amino group attached to the bicyclopentanering through an optionally substituted methylene. In some embodiments,R² cannot be a mono-substituted group directly attached to thebicyclopentane ring. In other embodiments, R² cannot be amono-substituted group attached to the bicyclopentane ring through anoptionally substituted methylene.

In some embodiments, R² cannot be C(═O)R^(2A). In some embodiments, R²cannot be an N-amido group directly attached to the bicyclopentane ring.In other embodiments, R² cannot be an N-amido group attached to thebicyclopentane ring through an optionally substituted methylene.

In some embodiments, R^(2A) cannot be H. In other embodiments, R^(2A)cannot be D. In still other embodiments, R^(2A) cannot be a substitutedC₁₋₃₀ alkyl. In yet still other embodiments, R^(2A) cannot be anunsubstituted C₁₋₃₀ alkyl.

In some embodiments, R^(2A) cannot be a substituted C₂₋₃₀ alkenyl. Inother embodiments, R^(2A) cannot be an unsubstituted C₂₋₃₀ alkenyl. Instill other embodiments, R^(2A) cannot be a substituted C₂₋₃₀ alkynyl.In yet still other embodiments, R^(2A) cannot be an unsubstituted C₂₋₃₀alkynyl.

In some embodiments, R^(2A) cannot be a substituted C₃₋₃₀ cycloalkyl. Inother embodiments, R^(2A) cannot be an unsubstituted C₃₋₃₀ cycloalkyl.In still other embodiments, R^(2A) cannot be a substituted C₃₋₃₀cycloalkenyl. In yet still other embodiments, R^(2A) cannot be anunsubstituted C₃₋₃₀ cycloalkenyl. In some embodiments, R^(2A) cannot bea substituted C₈₋₃₀ cycloalkynyl. In some embodiments, R^(2A) cannot bean unsubstituted C₈₋₃₀ cycloalkynyl. In some embodiments, a cycloalkyl,a cycloalkenyl and/or a cycloalkynyl can be mono-cyclic. In otherembodiments, a cycloalkyl, a cycloalkenyl and a cycloalkynyl can bebi-cyclic or tri-cyclic. As described herein, the rings of amulti-cyclic cycloalkyl, cycloalkenyl and cycloalkynyl can be joinedtogether in a fused, bridged and/or spiro fashion.

In some embodiments, R^(2A) cannot be a substituted C₆₋₃₀ aryl. In otherembodiments, R^(2A) cannot be an unsubstituted C₆₋₃₀ aryl. In someembodiments, R^(2A) cannot be a substituted or unsubstituted phenyl.

In some embodiments, R^(2A) cannot be a substituted heteroaryl. In otherembodiments, R^(2A) cannot be an unsubstituted heteroaryl. In someembodiments, R^(2A) cannot be a substituted or unsubstituted mono-cyclicheteroaryl. In some embodiments, R^(2A) cannot be a substituted orunsubstituted multi-cyclic heteroaryl, such as, a substituted orunsubstituted bi-cyclic heteroaryl.

In some embodiments, R^(2A) cannot be a substituted heterocyclyl. Inother embodiments, R^(2A) cannot be an unsubstituted heterocyclyl. Insome embodiments, R^(2A) cannot be a substituted or unsubstitutedmono-cyclic heterocyclyl. In some embodiments, R^(2A) cannot be asubstituted or unsubstituted multi-cyclic heterocyclyl (such as abi-cyclic heterocyclyl).

In some embodiments, R^(2A) cannot be a substituted aryl(C₁₋₆ alkyl). Inother embodiments, R^(2A) cannot be an unsubstituted aryl(C₁₋₆ alkyl).In some embodiments, R^(2A) cannot be a substituted or unsubstitutedbenzyl. In some embodiments, R^(2A) cannot be a substitutedheteroaryl(C₁₋₆ alkyl). In other embodiments, R^(2A) cannot be anunsubstituted heteroaryl(C₁₋₆ alkyl). In some embodiments, R^(2A) cannotbe a substituted or unsubstituted mono-cyclic heteroaryl(C₁₋₆ alkyl). Insome embodiments, R^(2A) cannot be a substituted or unsubstitutedmulti-cyclic heteroaryl(C₁₋₆ alkyl), such as a substituted orunsubstituted bi-cyclic heteroaryl(C₁₋₆ alkyl). In some embodiments,R^(2A) cannot be a substituted heterocyclyl(C₁₋₆ alkyl). In otherembodiments, R^(2A) cannot be an unsubstituted heterocyclyl(C₁₋₆ alkyl).In some embodiments, R^(2A) cannot be a substituted or unsubstitutedmono-cyclic heterocyclyl(C₁₋₆ alkyl). In some embodiments, R^(2A) cannotbe a substituted or unsubstituted multi-cyclic heterocyclyl(C₁₋₆ alkyl),for example, a substituted or unsubstituted bi-cyclic heterocyclyl(C₁₋₆alkyl).

In some embodiments, R^(2A) cannot be a substituted C₁₋₈ haloalkyl. Inother embodiments, R^(2A) cannot be an unsubstituted C₁₋₈ haloalkyl. Insome embodiments, R^(2A) cannot be one or more of the following CF₃,CHF₂, CH₂F, CH₂CF₃, CH₂CHF₂ and CH₂CH₂F.

In some embodiments, R³ cannot be H. In other embodiments, R³ cannot beD. In still other embodiments, R³ cannot be a halo. In some embodiments,R³ cannot be F. In some embodiments, R³ cannot Cl. In yet still otherembodiments, R³ cannot be hydroxy.

In some embodiments, R³ cannot be a substituted C₁₋₈ alkyl. In otherembodiments, R³ cannot be an unsubstituted C₁₋₈ alkyl.

In some embodiments, R³ cannot be a substituted C₂₋₈ alkenyl. In otherembodiments, R³ cannot be an unsubstituted C₂₋₈ alkenyl. In someembodiments, R³ cannot be a substituted C₂₋₄ alkenyl. In otherembodiments, R³ cannot be an unsubstituted C₂₋₄ alkenyl. In someembodiments, R³ cannot be a substituted C₂₋₈ alkynyl. In otherembodiments, R³ cannot be an unsubstituted C₂₋₈ alkynyl. In someembodiments, R³ cannot be a substituted C₂₋₄ alkynyl. In otherembodiments, R³ cannot be an unsubstituted C₂₋₄ alkynyl.

In some embodiments, R³ cannot be a substituted C₃₋₂₀ cycloalkyl. Inother embodiments, R³ cannot be an unsubstituted C₃₋₂₀ cycloalkyl. Insome embodiments, R³ cannot be a substituted C₃₋₂₀ cycloalkenyl. Inother embodiments, R³ cannot be an unsubstituted C₃₋₂₀ cycloalkenyl. Insome embodiments, R³ cannot be a substituted C₃₋₂₀ cycloalkynyl. Inother embodiments, R³ cannot be an unsubstituted C₃₋₂₀ cycloalkynyl.

In some embodiments, R³ cannot be a substituted C₆₋₂₀ aryl. In otherembodiments, R³ cannot be an unsubstituted C₆₋₂₀ aryl. In someembodiments, R³ cannot be an unsubstituted phenyl. In other embodiments,R³ cannot be a substituted phenyl. In some embodiments, R³ cannot be asubstituted naphthyl. In other embodiments, R³ cannot be anunsubstituted naphthyl.

In some embodiments, R³ cannot be a substituted heteroaryl. In otherembodiments, R³ cannot be an unsubstituted heteroaryl. In someembodiments, R³ cannot be a substituted mono-cyclic heteroaryl. In otherembodiments, R³ cannot be an unsubstituted mono-cyclic heteroaryl. Instill other embodiments, R³ cannot be a substituted multi-cyclicheteroaryl (for example, a substituted bi-cyclic heteroaryl). In yetstill other embodiments, R³ cannot be an unsubstituted multi-cyclicheteroaryl (for example, an unsubstituted bi-cyclic heteroaryl).

In some embodiments, R³ cannot be a substituted heterocyclyl. In otherembodiments, R³ cannot be an unsubstituted heterocyclyl. In someembodiments, R³ cannot be a substituted mono-cyclic heterocyclyl. Inother embodiments, R³ cannot be an unsubstituted mono-cyclicheterocyclyl. In still other embodiments, R³ cannot be a substitutedbi-cyclic heterocyclyl. In yet still other embodiments, R³ cannot be anunsubstituted bi-cyclic heterocyclyl.

In some embodiments, R³ cannot be a substituted aryl(C₁₋₆ alkyl). Inother embodiments, R³ cannot be an unsubstituted aryl(C₁₋₆ alkyl). Insome embodiments, R³ cannot be a substituted or unsubstituted benzyl.

In some embodiments, R³ cannot be a substituted heteroaryl(C₁₋₆ alkyl).In other embodiments, R³ cannot be an unsubstituted heteroaryl(C₁₋₆alkyl). In still other embodiments, R³ cannot be a substitutedheterocyclyl(C₁₋₆ alkyl). In other embodiments, R³ cannot be anunsubstituted heterocyclyl(C₁₋₆ alkyl). In some embodiments, R³ cannotbe a substituted mono-cyclic heterocyclyl(C₁₋₆ alkyl). In otherembodiments, R³ cannot be an unsubstituted mono-cyclic heterocyclyl(C₁₋₆alkyl). In still other embodiments, R³ cannot be a substitutedmulti-cyclic heterocyclyl(C₁₋₆ alkyl), such as, a substituted bi-cyclicheterocyclyl(C₁₋₆ alkyl). In yet still other embodiments, R³ cannot bean unsubstituted multi-cyclic heterocyclyl(C₁₋₆ alkyl), such as, anunsubstituted bi-cyclic heterocyclyl(C₁₋₆ alkyl).

In some embodiments, R³ cannot be a substituted C₁₋₈ haloalkyl. In otherembodiments, R³ cannot be an unsubstituted C₁₋₈ haloalkyl. In someembodiments, R³ cannot be CF₃.

In some embodiments, R³ cannot be a substituted sulfonyl. In otherembodiments, R³ cannot be an unsubstituted sulfonyl. In someembodiments, R³ cannot be SO₂R⁺⁺, wherein R⁺⁺ can be hydrogen, anoptionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆alkenyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted mono-cyclic aryl, an optionally substituted mono-cyclicheteroaryl or an optionally substituted mono-cyclic heterocyclyl. Inother embodiments, R³ cannot be SO₂R⁺⁺, wherein R⁺⁺ can be anunsubstituted C₁₋₆ alkyl, an unsubstituted C₂₋₆ alkenyl or anunsubstituted C₃₋₆ cycloalkyl. In some embodiments, R³ cannot be SO₂CH₃.

In some embodiments, m cannot be 0. In other embodiments, m cannot be 1.In still other embodiments, m cannot be 2. In yet still otherembodiments, m cannot be 3. In some embodiments, R⁴ cannot be H. Inother embodiments, R⁴ cannot be D. In still other embodiments, R⁴ cannotbe an unsubstituted C₁₋₈ alkyl. In yet still other embodiments, R⁴cannot be an unsubstituted C₁₋₆ haloalkyl, such as CF₃, CHF₂ or CH₂F. Insome embodiments, R⁵ cannot be H. In other embodiments, R⁵ cannot be D.In other embodiments, R⁵ cannot be an unsubstituted C₁₋₈ alkyl. In yetstill other embodiments, R⁵ cannot be an unsubstituted C₁₋₆ haloalkyl,such as CF₃, CHF₂ or CH₂F. In some embodiments, R⁴ and R⁵ cannot betaken together to form an optionally substituted C₃₋₆ cycloalkyl.

Other embodiments disclosed herein relate to a compound of Formula (II),or a pharmaceutically acceptable salt thereof:

wherein: R^(1b) can be H or CH₃; R^(2b) can be CH₂F, CHF₂, CF₃ or anunsubstituted C₁₋₄ alkyl; and R^(3b) can be H, CH₂F, CHF₂, CF₃, anunsubstituted C₁₋₄ alkyl or a hydro-substituted C₁₋₄ alkyl.

In some embodiments, R^(1b) can be H. In other embodiments, R^(1b) canbe CH₃.

In some embodiments, R^(2b) can be CH₂F. In other embodiments, R^(2b)can be CHF₂. In still other embodiments, R^(2b) can be CF₃. In yet stillother embodiments, R^(2b) can be an unsubstituted C₁₋₄ alkyl (such asmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl).

In some embodiments, R^(3b) can be H. In other embodiments, R^(3b) canbe CH₂F. In still other embodiments, R^(3b) can be CHF₂. In yet stillother embodiments, R^(3b) can be CF₃. In some embodiments, R^(3b) can bean unsubstituted C₁₋₄ alkyl, for example, methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl and tert-butyl. In other embodiments,R^(3b) can be a hydro-substituted C₁₋₄ alkyl, for example, —C(CH₃)₂OH.

In some embodiments, R^(1b) can be H or CH₃; R^(2b) can be CH₂F, CHF₂,CF₃ or an unsubstituted C₁₋₄ alkyl; and R^(3b) can be CH₂F, CHF₂ or CF₃.In some embodiments, R^(1b) can be H or CH₃; R^(2b) can be CH₂F, CHF₂,CF₃ or an unsubstituted C₁₋₄ alkyl; and R^(3b) can be an unsubstitutedC₁₋₄ alkyl or a hydro-substituted C₁₋₄ alkyl. In some embodiments,R^(1b) can be H or CH₃; R^(2b) can be an unsubstituted C₁₋₄ alkyl; andR^(3b) can be an unsubstituted C₁₋₄ alkyl or a hydro-substituted C₁₋₄alkyl. In some embodiments, R^(1b) can be H or CH₃; R^(2b) can be CH₂F,CHF₂ or CF₃; and R^(3b) can be an unsubstituted C₁₋₄ alkyl or ahydro-substituted C₁₋₄ alkyl.

Examples of compounds of Formula (II) include, but are not limited to:

or a pharmaceutically acceptable salt of the foregoing.

Methods

The various compounds contemplated herein can be synthesized from knownstarting materials by various routes. Some suitable routes areillustrated in Schemes 1 and 2, with syntheses described in more detailin the following description and Examples.

As shown in Scheme 1, compounds of Formula (I) can be prepared startingfrom a compound of Formula (A). The reaction of a compound of Formula(A) with a Grignard reagent followed by trapping with an electrophilesuch as carbon dioxide leads to a carboxylic acid compound. Thecarboxylic acid compound can be transformed to a carboxamide through anamide bond formation reaction with ammonia as the amine source. Thecarboxamide compound can be reduced using standard reducing reagentssuch as lithium aluminum hydride to give a primary amine. A second amidebond formation reaction with various reagents such as carboxylic acids,acid chlorides, or acid anhydrides leads to compounds of Formula (I).

For example, the reaction of [1.1.1]propellane with tert-butylmagnesiumchloride followed by quenching the reaction with carbon dioxide gives3-(tert-butyl)bicyclo[1.1.1]pentane-1-carboxylic acid. The conversion of3-(tert-butyl)bicyclo[1.1.1]pentane-1-carboxylic acid to3-(tert-butyl)bicyclo[1.1.1]pentane-1-carboxamide can be carried outusing various amide bond formation reactions, for example by forming anacid chloride using reagents such as thionyl chloride or oxalyl chlorideand then treating the formed3-(tert-butyl)bicyclo[1.1.1]pentane-1-carbonyl chloride with ammonia.The reduction of 3-(tert-butyl)bicyclo[1.1.1]pentane-1-carboxamide canbe carried out using such reagents as lithium aluminum hydride to give(3-(tert-butyl)bicyclo[1.1.1]pentan-1-yl)methanamine. The treatment of(3-(tert-butyl)bicyclo[1.1.1]pentan-1-yl)methanamine with reagents suchas acetic anhydride or acetyl chloride givesN-((3-(tert-butyl)bicyclo[1.1.1]pentan-1-yl)methyl)acetamide.

Compounds of Formula (I) can also be prepared starting from a compoundof Formula (A) via the route shown in Scheme 2. Compound of Formula (A)can be reacted with methyl lithium and R³X in ether, wherein X is asuitable leaving group (for example, a halogen). A carboxylic acidmoiety can be formed using t-butyl lithium and carbon dioxide. Thecarboxylic acid compound can be transformed and form a protected aminevia a Curtius rearrangement using an azide, a reagent(s) that canprovide the protecting group and a base, such as diphenylphosphorylazide (DPPA), t-BuOH and triethyl amine, respectively. The protectinggroup can be removed using methods known to those skilled in the art,such as an acid. If desired and/or needed, the carboxylic acid compoundcan be converted to a carboxylic acid chloride before forming theprotected amine.

Salts can be formed using methods known to those skilled in the art anddescribed herein, for example, reacting an amine with a suitable acid(such as HCl).

Pharmaceutical Compositions

Some embodiments described herein relate to a pharmaceuticalcomposition, that can include an effective amount of one or morecompounds described herein (e.g., a compound of Formulae (I) and/or(II), or a pharmaceutically acceptable salt thereof) and apharmaceutically acceptable carrier, diluent, excipient or combinationthereof.

The term “pharmaceutical composition” refers to a mixture of one or morecompounds disclosed herein with other chemical components, such asdiluents or carriers. The pharmaceutical composition facilitatesadministration of the compound to an organism. Pharmaceuticalcompositions can also be obtained by reacting compounds with inorganicor organic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonicacid, p-toluenesulfonic acid, and salicylic acid. Pharmaceuticalcompositions will generally be tailored to the specific intended routeof administration.

The term “physiologically acceptable” defines a carrier, diluent orexcipient that does not abrogate the biological activity and propertiesof the compound nor cause appreciable damage or injury to an animal towhich delivery of the composition is intended.

As used herein, a “carrier” refers to a compound that facilitates theincorporation of a compound into cells or tissues. For example, withoutlimitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrierthat facilitates the uptake of many organic compounds into cells ortissues of a subject.

As used herein, a “diluent” refers to an ingredient in a pharmaceuticalcomposition that lacks appreciable pharmacological activity but may bepharmaceutically necessary or desirable. For example, a diluent may beused to increase the bulk of a potent drug whose mass is too small formanufacture and/or administration. It may also be a liquid for thedissolution of a drug to be administered by injection, ingestion orinhalation. A common form of diluent in the art is a buffered aqueoussolution such as, without limitation, phosphate buffered saline thatmimics the pH and isotonicity of human blood.

As used herein, an “excipient” refers to an essentially inert substancethat is added to a pharmaceutical composition to provide, withoutlimitation, bulk, consistency, stability, binding ability, lubrication,disintegrating ability etc., to the composition. A “diluent” is a typeof excipient.

The pharmaceutical compositions described herein can be administered toa human patient per se, or in pharmaceutical compositions where they aremixed with other active ingredients, as in combination therapy, orcarriers, diluents, excipients or combinations thereof. Properformulation is dependent upon the route of administration chosen.Techniques for formulation and administration of the compounds describedherein are known to those skilled in the art.

The pharmaceutical compositions disclosed herein may be manufactured ina manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or tableting processes. Additionally, theactive ingredients are contained in an amount effective to achieve itsintended purpose. Many of the compounds used in the pharmaceuticalcombinations disclosed herein may be provided as salts withpharmaceutically compatible counterions.

Multiple techniques of administering a compound exist in the artincluding, but not limited to, oral, rectal, pulmonary, topical,aerosol, injection, infusion and parenteral delivery, includingintramuscular, subcutaneous, intravenous, intramedullary injections,intrathecal, direct intraventricular, intraperitoneal, intranasal andintraocular injections.

One may also administer the compound in a local rather than systemicmanner, for example, via injection or implantation of the compounddirectly into the affected area, often in a depot or sustained releaseformulation. Furthermore, one may administer the compound in a targeteddrug delivery system, for example, in a liposome coated with atissue-specific antibody. The liposomes will be targeted to and taken upselectively by the organ. For example, intranasal or pulmonary deliveryto target a respiratory infection may be desirable.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. The pack or dispensermay also be accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, may be the labeling approvedby the U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. Compositions that can include a compounddescribed herein formulated in a compatible pharmaceutical carrier mayalso be prepared, placed in an appropriate container, and labeled fortreatment of an indicated condition.

Methods of Use

Some embodiments provided herein relate to a method of treating adisease or condition that can include administering to a subject aneffective amount of a compound of Formulae (I) and/or (II), or apharmaceutically acceptable salt thereof. Other embodiments providedherein relate to a method of treating a disease or condition that caninclude contacting a cell in the central and/or peripheral nervoussystem of a subject with an effective amount of a compound of Formulae(I) and/or (II), or a pharmaceutically acceptable salt thereof. In someembodiments, the subject can be at risk of developing a disease orcondition that is responsive to acetaminophen and/or a NSAID. In someembodiments, the disease or condition can be one or more of thefollowing: pain, fever, inflammation, ischemic injury (such asmyocardial and/or cerebral) and/or neuronal injury. In some embodiments,the subject can be post-operative and has, or is believed to have or hasactually developed post-operative pain. In some embodiments, a compoundof Formulae (I) and/or (II), or a pharmaceutically acceptable saltthereof, can be provided (such as administered) prophylactically, forexample, prophylactically for pain (such as post-operative pain).

In some embodiments, a compound of Formulae (I) and/or (II), or apharmaceutically acceptable salt thereof, can contact a cell in thecentral nervous system, for example, the brain and/or spinal cord. Insome embodiments, a compound of Formulae (I) and/or (II), or apharmaceutically acceptable salt thereof, can contact a cell in theperipheral nervous system, for example, the ganglia and/or nervoussystem outside the brain and spinal cord.

In some embodiments, a compound of Formulae (I) and/or (II), or apharmaceutically acceptable salt thereof, can contact a TRP (transientreceptor potential) channels modulator (such as TRPV1 and/or TRPA1), andthereby treat a disease or condition described herein. In someembodiments, a compound of Formulae (I) and/or (II), or apharmaceutically acceptable salt thereof, can contact a cannabinoidreceptors modulator (such as CB1 and/or CB2), and thereby treat adisease or condition described herein. In some embodiments, a compoundof Formulae (I) and/or (II), or a pharmaceutically acceptable saltthereof, can contact a serotonin receptor (for example, 5HT1, 5HT2,5HT3, 5HT4, 5HT5, 5HT6 and/or 5HT7) and modulate its activity, andthereby treat a disease or condition described herein. In someembodiments, a compound of Formulae (I) and/or (II), or apharmaceutically acceptable salt thereof, can act as an anandamidereuptake inhibitor, and thereby treat a disease or condition describedherein. In some embodiments, a compound of Formulae (I) and/or (II), ora pharmaceutically acceptable salt thereof, can be a substrate for thefatty acid amide hydrolase (FAAH), and thereby treat a disease orcondition described herein.

Some embodiments generally related to a method of treating pain of anyetiology, including acute and chronic pain, and any pain in whichacetaminophen is prescribed. Examples of pain include post-surgicalpain; post-operative pain (including dental pain); migraine; headacheand trigeminal neuralgia; pain associated with burn, wound and/or kidneystone; pain associated with trauma (including traumatic head injury);neuropathic pain (e.g., central and peripheral pain); pain associatedwith musculo-skeletal disorders; strains; sprains; contusions;fractures; myalgia; nociceptive pain (for example, rheumatoid arthritisand osteoarthritis); cystitis; visceral pain (such as, pancreatitis,inflammatory bowel disease and internal organ pain); ankylosingspondylitis; sero-negative (non-rheumatoid) arthropathies; non-articularrheumatism and peri-articular disorders; and mixed pain. Central painincludes post-stroke pain, pain associated with multiple sclerosis,spinal cord injury, migraine and HIV-related neuropathic pain.Peripheral pain includes postherpetic neuralgia and diabetic neuropathy.Mixed pain includes pain associated with cancer (including“break-through pain” and pain associated with terminal cancer), lowerback and fibromyalgia. Examples of pain with an inflammatory component(in addition to some of those described above) include rheumatic pain,pain associated with mucositis and pain associated with dysmenorrhea. Insome embodiments, a method and/or a composition described herein can beused for treating or preventing post-surgical pain. In some embodiments,a method and/or a composition described herein can be used for treatingor preventing of cancer pain. In some embodiments, a method and/or acomposition described herein can be used for treating or preventing ofosteoarthritis and/or rheumatoid arthritis pain.

In some embodiments, a method and/or a composition described herein canbe used for treating or preventing of migraine pain. In someembodiments, a method and/or a composition described herein can be usedfor treating or preventing of lower back pain and/or fibromyalgia pain.In some embodiments, a method and/or a composition described herein canbe used for treating or preventing pain that is selected from painassociated with surgery, trauma, osteoarthritis, rheumatoid arthritis,lower back pain, fibromyalgia, postherpetic neuralgia, diabeticneuropathy, HIV-associated neuropathy and complex regional painsyndrome. Additionally information regarding pain is provided inMelnikova, I., “Pain market” (2010) 9(8):589-590, which is herebyincorporated by reference in its entirety.

In some embodiments, a compound of Formulae (I) and/or (II), or apharmaceutically acceptable salt thereof, can be used for treating orpreventing pain and/or a fever (e.g., in adults, children and/orinfants). Compounds of Formulae (I) and/or (II), or pharmaceuticallyacceptable salts thereof, can be used to treat a variety and varyingdegrees of pain. In some embodiments, the pain can be acute pain (e.g.,acute pain following surgery, such as orthopedic surgery of adults,children, and/or infants).

In some embodiments, a compound of Formulae (I) and/or (II), or apharmaceutically acceptable salt thereof, can be used for treatingand/or preventing a fever, such as endotoxin-induced fever (e.g.,endotoxin-induced fever in adults, children, and/or infants). In someembodiments, the fever can be selected from low-grade fever, moderatefever, high-grade fever and hyperpyrexia fever. In some embodiments, thefever can be selected from Pel-Ebstein fever, continuous fever,intermittent fever and remittent fever.

As described herein, compounds of Formulae (I) and/or (II), orpharmaceutically acceptable salts thereof, can be used in a varioussubjects. In some embodiments, the subject can be a child and/or aninfant, for example, a child or infant with a fever. In otherembodiments, the subject can be an adult.

Some embodiments described herein relate to a method of delaying theonset of analgesia in a subject in need thereof, wherein the method caninclude administering to the subject an effective amount of Formulae (I)and/or (II) that delays drug action by greater than about 5 minutes, or10 minutes, or 15 minutes, or 30 minutes, or 1 hour, or 2, hours, or 3hours, or 4 hours, or 6 hours, or 8 hours, or 10 hours, or 12 hours, or18 hours, or 24 hours. Other embodiments described herein relate to amethod of delaying the onset of analgesia in a subject in need thereof,wherein the method can include contacting a cell in the central and/orperipheral nervous system of a subject with an effective amount ofFormulae (I) and/or (II) that delays drug action by greater than about 5minutes, or 10 minutes, or 15 minutes, or 30 minutes, or 1 hour, or 2,hours, or 3 hours, or 4 hours, or 6 hours, or 8 hours, or 10 hours, or12 hours, or 18 hours, or 24 hours.

As described herein, compounds of Formulae (I) and/or (II), or apharmaceutically acceptable salt thereof, can be administered by avariety of methods. In any of the methods described herein,administration can be by injection, infusion and/or intravenousadministration over the course of 1 minute, 5 minutes, 10 minutes, 30minutes, 1 hour, 2 hours, 6 hours, 12 hours, 24 hours or longer, or anyintermediate time. Such administration can, in some circumstances,substitute for or significantly reduce the need for administration of anopiate. Some methods described herein can include intravenousadministration to a subject in need thereof, for example, to a subjectto manage post-operative or other acute or chronic pain, in either abolus dose or by infusion over minutes, hours, or days. Other methodsdescribed herein can include oral, intravenous and/or intraperitonealadministration to a subject in need thereof, for example, to a subjectto manage post-operative or other acute or chronic pain.

Other embodiments described herein relate to a method for selecting atherapy for managing or treating pain in a subject in need thereof, thatcan include evaluating whether the subject is at risk for hepatictoxicity from pain therapy, and selecting therapy that includes acompound of Formulae (I) and/or (II), or a pharmaceutically acceptablesalt thereof, to reduce or eliminate such risk. The method can furtherinclude providing the selected therapy that includes a compound ofFormulae (I) and/or (II), or a pharmaceutically acceptable salt thereof,to the subject. In some embodiments, a compound of Formulae (I) and/or(II), or a pharmaceutically acceptable salt thereof, can be ofsignificant benefit in pain management in hospitals or other carefacilities (for example, a nursing home).

As used herein, the terms “prevent” and “preventing,” mean a subjectdoes not experience and/or develop pain and/or fever, or the severity ofthe pain and/or fever is less compared to the severity of the painand/or fever if the subject has not been administered/received thecompound. Examples of forms of prevention include prophylacticadministration to a subject who is going to undergo surgery.

As used herein, the terms “treat,” “treating,” “treatment,”“therapeutic,” and “therapy” do not necessarily mean total cure orabolition of the disease or condition. Any alleviation of any undesiredsigns or symptoms of a disease or condition, to any extent can beconsidered treatment and/or therapy. Furthermore, treatment may includeacts that may worsen the subject's overall feeling of well-being orappearance.

The terms “therapeutically effective amount” and “effective amount” areused to indicate an amount of an active compound, or pharmaceuticalagent, that elicits the biological or medicinal response indicated. Forexample, a therapeutically effective amount of compound can be theamount needed to prevent, alleviate or ameliorate symptoms of disease orprolong the survival of the subject being treated This response mayoccur in a tissue, system, animal or human and includes alleviation ofthe signs or symptoms of the disease being treated. Determination of aneffective amount is well within the capability of those skilled in theart, in view of the disclosure provided herein. The therapeuticallyeffective amount of the compounds disclosed herein required as a dosewill depend on the route of administration, the type of animal,including human, being treated, and the physical characteristics of thespecific animal under consideration. The dose can be tailored to achievea desired effect, but will depend on such factors as weight, diet,concurrent medication and other factors which those skilled in themedical arts will recognize.

The amount of the compound, or an active salt or derivative thereof,required for use in treatment will vary not only with the particularsalt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician. In cases of administration of a pharmaceutically acceptablesalt, dosages may be calculated as the free base. As will be understoodby those of skill in the art, in certain situations it may be necessaryto administer the compounds disclosed herein in amounts that exceed, oreven far exceed, the above-stated, preferred dosage range in order toeffectively and aggressively treat particularly aggressive diseases orconditions.

In general, however, a suitable dose will often be in the range of fromabout 0.15 mg/kg to about 100 mg/kg. For example, a suitable dose may bein the range from about 1 mg/kg to about 75 mg/kg of body weight perday, such as about 0.75 mg/kg to about 50 mg/kg of body weight of therecipient per day, about 1 mg/kg to 90 mg/kg of body weight of therecipient per day, or about 10 mg/kg to about 60 mg/kg of body weight ofthe recipient per day.

The compound may be administered in unit dosage form; for example,containing 1 to 2000 mg, 10 to 1000 mg or 5 to 500 mg of activeingredient per unit dosage form.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations.

As will be readily apparent to one skilled in the art, the useful invivo dosage to be administered and the particular mode of administrationwill vary depending upon the age, weight, the severity of theaffliction, and mammalian species treated, the particular compoundsemployed, and the specific use for which these compounds are employed.The determination of effective dosage levels, that is the dosage levelsnecessary to achieve the desired result, can be accomplished by oneskilled in the art using routine methods, for example, human clinicaltrials, in vivo studies and in vitro studies. For example, usefuldosages of compounds of Formulae (I) and/or (II), or pharmaceuticallyacceptable salts thereof, can be determined by comparing their in vitroactivity, and in vivo activity in animal models. Such comparison can bedone against an established analgesic drug, such as acetaminophen.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain themodulating effects, or minimal effective concentration (MEC). The MECwill vary for each compound but can be estimated from in vivo and/or invitro data. Dosages necessary to achieve the MEC will depend onindividual characteristics and route of administration. However, HPLCassays or bioassays can be used to determine plasma concentrations.Dosage intervals can also be determined using MEC value. Compositionsshould be administered using a regimen which maintains plasma levelsabove the MEC for 10-90% of the time, preferably between 30-90% and mostpreferably between 50-90%. In cases of local administration or selectiveuptake, the effective local concentration of the drug may not be relatedto plasma concentration.

It should be noted that the attending physician would know how to andwhen to terminate, interrupt, or adjust administration due to toxicityor organ dysfunctions. Conversely, the attending physician would alsoknow to adjust treatment to higher levels if the clinical response werenot adequate (precluding toxicity). The magnitude of an administrateddose in the management of the disorder of interest will vary with theseverity of the condition to be treated and to the route ofadministration. The severity of the condition may, for example, beevaluated, in part, by standard prognostic evaluation methods. Further,the dose and perhaps dose frequency, will also vary according to theage, body weight, and response of the individual patient. A programcomparable to that discussed above may be used in veterinary medicine.

Compounds disclosed herein can be evaluated for efficacy and toxicityusing known methods. For example, the toxicology of a particularcompound, or of a subset of the compounds, sharing certain chemicalmoieties, may be established by determining in vitro toxicity towards acell line, such as a mammalian, and preferably human, cell line. Theresults of such studies are often predictive of toxicity in animals,such as mammals, or more specifically, humans. Alternatively, thetoxicity of particular compounds in an animal model, such as mice, rats,rabbits, dogs or monkeys, may be determined using known methods. Theefficacy of a particular compound may be established using severalrecognized methods, such as in vitro methods, animal models, or humanclinical trials. When selecting a model to determine efficacy, theskilled artisan can be guided by the state of the art to choose anappropriate model, dose, route of administration and/or regime.

Combination Drugs

One or more compounds of Formulae (I) and/or (II), or a pharmaceuticallyacceptable salt thereof, can be provided alone or in combination withanother drug(s). In some embodiments, the other drug(s) can be an opioidanalgesic. Any of the known opioid analgesics can be combined with acompound of Formulae (I) and/or (II), or a pharmaceutically acceptablesalt thereof. As non-limiting examples, such opioid analgesics includemorphine, codeine, hydrocodone, oxycodone, fentanyl, pethidine,methadone, pentazocine, sufentanil, levorphanol, dihydrocodeine,nalbuphine, butorphanol, tramadol, meptazinol, buprenorphine,dipipanone, alfentanil, remifentanil, oxymorphone, tapentadol,propoxyphene and hydromorphone.

In some embodiments, a compound of Formulae (I) and/or (II), or apharmaceutically acceptable salt thereof, can be provided in a dosageform (for example, an oral dosage form, an intravenous dosage formand/or an intraperitoneal dosage form), in combination with one of thefollowing exemplary opioids: 1-20 mg hydrocodone (such as hydrocodonebitartrate), preferably 2.5 mg, 5 mg, 7.5 mg or 10 mg of hydrocodone orsalt thereof; or 1-20 mg oxycodone, preferably 2.5 mg, 5 mg, 7.5 mg or10 mg of hydrocodone or salt thereof (such as the hydrochloride salt).In some embodiments, the amount of a compound of Formulae (I) and/or(II), or a pharmaceutically acceptable salt thereof, can be in the rangeof about 20 to about 2000 mg.

Other combinations include combination of a compound of Formulae (I)and/or (II), or a pharmaceutically acceptable salt thereof, withbutalbital, codeine, dihydrocodeine, ibuprofen, aspirin and/or naproxen.The other drug(s) can be provided using routes known to those skilled inthe art and/or described herein. In some embodiments, a compound ofFormulae (I) and/or (II), or a pharmaceutically acceptable salt thereof,and another drug(s) can be provided in the same dosage form. In otherembodiments, a compound of Formulae (I) and/or (II), or apharmaceutically acceptable salt thereof, and another drug(s) can beprovided in the separate dosage forms. In some embodiments, a compoundof Formulae (I) and/or (II), or a pharmaceutically acceptable saltthereof, and another drug(s) can be by the same route (for example, bothintravenously) or by different routes (for example, one orally and theother intraperitoneally). In some embodiments, a compound of Formulae(I) and/or (II), or a pharmaceutically acceptable salt thereof, can beprovided before another drug(s) (such as an opiate). In otherembodiments, a compound of Formulae (I) and/or (II), or apharmaceutically acceptable salt thereof, can be provided simultaneouslywith another drug(s) (such as an opiate). In still other embodiments, acompound of Formulae (I) and/or (II), or a pharmaceutically acceptablesalt thereof, can be provided after another drug(s) (such as an opiate).

In some embodiments, a combination of a compound of Formulae (I) and/or(II), or a pharmaceutically acceptable salt thereof, and an opioidanalgesic can synergistically relieve pain. In some embodiments, thesynergistic relief of pain can reduce opioid use. Some embodimentsdisclosed herein relate to a method of managing, treating and/orreducing pain that can include administering an effective amount of acombination of a compound of Formulae (I) and/or (II), or apharmaceutically acceptable salt thereof, and an opioid analgesic to asubject. Some embodiments disclosed herein relate to a method forreducing opioid use in pain management, that can include administeringan amount of a compound of Formulae (I) and/or (II), or apharmaceutically acceptable salt thereof, in combination with an amountof an opioid analgesic, wherein the amount of the opioid analgesic inthe combination is less than the amount of opioid analgesic needed toachieve approximately the same level of pain management when the opioidanalgesic is administered alone. Methods known for evaluating painmanagement is known to those skilled in the art, for example, painassessment tools. Some embodiments disclosed herein relate to a methodfor decreasing the risk of opioid dependency that can includeadministering an amount of a compound of Formulae (I) and/or (II), or apharmaceutically acceptable salt thereof, in combination with an amountof an opioid analgesic, wherein the amount of the opioid analgesic inthe combination is less than the amount of opioid analgesic needed toachieve approximately the same level of pain management when the opioidanalgesic is administered alone. Some embodiments disclosed hereinrelate to a method for treating pain and/or fever along with treatingopioid dependency that can include administering an amount of a compoundof Formulae (I) and/or (II), or a pharmaceutically acceptable saltthereof, in combination with an amount of an opioid analgesic.

EXAMPLES

Additional embodiments are disclosed in further detail in the followingexamples, which are not in any way intended to limit the scope of theclaims.

Example 1 Compound 1

To a solution of propellane (0.311 M in Et₂O/pentane, 0.400 g, 6.05mmol, 19.5 mL) cooled to −50° C. was added dropwise tert-butylmagnesiumchloride (2.0 M in Et₂O, 0.710 g, 6.05 mmol, 3.03 mL). The solution wasallowed to warm to room temperature (rt) and stirred for 4 d. After 4 d,the solution was cooled to 0° C. and CO₂ was rapidly bubbled through thesolution for 10 mins. The solution was allowed to warm to rt and thenthe mixture was washed with H₂O (3×20 mL). The combined aqueous layerswere acidified with HCl (acidic by pH paper). Brine (15 mL) was added,and the mixture was extracted with EtOAc (4×20 mL). The combinedorganics were dried (Na₂SO₄) and concentrated under reduced pressure toafford 1a (0.748 g, 74%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ12.22 (s, COOH, 1H), 1.72 (s, 6H), 0.81 (s, 9H).

To a solution of 1a (0.8 g, 4.76 mmol) in 1,2-DCE (25 mL) and DMF (0.08mL) was added oxalyl chloride (0.9 mL, 10.5 mmol) dropwise. A gasevolution was observed, and the reaction became a clear light yellowsolution. Gas evolution subsided after 10 mins, and the reaction wasstirred at rt. After 3 h, the reaction was cooled to 0° C. and anammonium hydroxide solution (28% NH₃ in H₂O, 16.0 mL, 237.8 mmol) wasadded rapidly to the solution via syringe. The reaction was stirredovernight at rt. After 16 h, the reaction was filtered, and thecollected solid was washed with DCM. The aqueous layer was washed DCM(2×). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to provide 1b (0.772 g, 91%) as a light yellowsolid. ¹H-NMR (400 MHz, CDCl₃) δ 1.83 (s, 3H), 0.85 (s, 6H); LC/MS(APCI) m/z 168.1 [C₁₀H₁₇NO+H]⁺.

A solution of 1b (0.772 g, 4.62 mmol) in THF (23 mL) was cooled to 0° C.and treated with LiAlH₄ (2M in THF, 5.1 mL, 10.2 mmol) dropwise. Gasevolution was observed over the 5 mins. Following the addition, thereaction was warmed to rt. After 17 h, the reaction was cooled to 0° C.and treated with H₂O (386 μL), followed by 15% w/v aqueous NaOH solution(386 μL) and H₂O (1.2 mL). The reaction was stirred for 45 mins at rt.The reaction was filtered, and the collected aluminum salts were washedwith EtOAc. The combined filtrates were treated with Na₂SO₄ and weresubsequently filtered. The filtrate was cooled to 0° C. and HCl (4M indioxane, 5.8 mL, 23.1 mmol) was added dropwise. The reaction was stirredat rt for 30 min and then concentrated in vacuo to provide a whitesolid. The white solid was triturated with Et₂O to provide 1c (655 mg,75%) as a white solid. ¹H-NMR (400 MHz, CD₃OD) δ 3.01 (s, 2H), 1.62 (s,6H), 0.88 (s, 9H); LC/MS (APCI) m/z

A solution of 1c (0.140 g, 0.74 mmol) in DCM (3.7 mL) and sat. aq.NaHCO₃ (11.1 mL) at 0° C. was treated with acetic anhydride (0.350 mL,3.7 mmol). The mixture was stirred at 0° C. After 2.5 h, the reactionwas complete as indicated by LCMS. The mixture was extracted with DCM(3×15 mL). The combined organics were washed with H₂O (20 mL) and brine(20 mL), dried (MgSO₄) and concentrated under reduced pressure to affordthe crude product that was further purified by SiO₂ chromatography(0-60% EtOAc/Hexanes) to provide 1 (76.7 mg, 53%) as a white solid.¹H-NMR (400 MHz, DMSO-d6) δ 7.70 (br s, 1H), 3.10 (d, J=5.6 Hz, 2H),1.80 (s, 3H), 1.38 (s, 6H), 0.80 (s, 9H); LC/MS (APCI) m/z 196.1[C₁₂H₂₁NO+H]⁺.

Example 2 Compound 2

Trifluoromethyliodide (1.96 g, 9.98 mmol, 0.768 mL) was condensed into apressure vessel at −78° C. A solution of propellane (0.211 M in Et₂O,0.300 g, 4.54 mmol, 21.5 mL) at −78° C. was cannulated over, and thevessel was sealed and allowed to warm to rt. The solution was allowed tostand for 3 d at rt and protected from light. The volatiles were removedat 0° C. under reduced pressure to provide the crude product as anoff-white solid. Hexanes (15 mL) were added, and the solution was cooledto −78° C. at which time the product precipitated out as a white solid.The solid was then washed with cold (−78° C.) hexanes (3×5 mL), and theproduct was dried under a slight vacuum to afford 2a (1.022 g. 86%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 2.47 (s, 6H).

1-(Trifluoromethyl)-3-iodobicyclo[1.1.1]pentane (1.02 g, 3.89 mmol) wasdissolved in anhydrous diethyl ether (13.0 mL) and cooled to −78° C. Asolution of tBuLi (1.7 M in pentane, 0.549 g, 8.56 mmol, 5.04 mL) wasadded slowly, and the solution was stirred at −78° C. After 30 mins, CO₂was bubbled through the solution for 10 mins, and the reaction wasallowed to warm to rt. Diethyl ether (10 mL) was added, and the mixturewas extracted with H₂O (3×20 mL). The combined aqueous layers wereacidified with 2M HCl then extracted with Et₂O (3×20 mL). The combinedorganics were dried (MgSO₄) and concentrated under reduced pressure toafford 2b (0.603 g, 86%) as a white solid which was carried forwardwithout further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 12.77 (br s,COOH, 1H), 2.20 (s, 6H).

To a solution of 2b (0.9 g, 4.76 mmol) in 1,2-DCE (17 mL) and DMF (0.040mL) was added oxalyl chloride (0.93 mL, 11.0 mmol) dropwise. Gasevolution was observed, and the reaction became a clear light yellowsolution. Gas evolution subsided after 5 mins, and the reaction wasstirred at rt. After 2 h, the reaction was cooled to 0° C. and anammonium hydroxide solution (28% NH₃ in H₂O, 16.9 mL, 249.8 mmol) wasadded rapidly to the solution by syringe. The reaction was stirredovernight at rt. After 16 h, the reaction was filtered, and thecollected solid was washed with water (40 mL) and 95:5 EtOAc:MeOH (200mL). The aqueous layer was washed with 95:5 EtOAc:MeOH (2×). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to provide 2c (0.690 g, 77%) as a white solid.¹H-NMR (400 MHz, DMSO-d6) δ 7.44 (s, 1H), 7.14 (s, 1H), 2.12 (s, 6H);LC/MS (APCI) m/z 180.0 [C₇H₈F₃NO+H]⁺.

A solution of 2c (0.597 g, 3.34 mmol) in THF (24 mL) was cooled to 0° C.and treated with LiAlH₄ (2 M in THF, 4.2 mL, 16.7 mmol) dropwise. Gasevolution was observed over 5 mins. The reaction was warmed to rt. After17 h, the reaction was cooled to 0° C. and treated with H₂O (300 μL),followed by 15% w/v aqueous NaOH solution (300 μL) and H₂O (900 mL). Thereaction was stirred for 45 mins at rt. The mixture was filtered, andthe collected aluminum salts were washed with EtOAc. The combinedfiltrates were treated with Na₂SO₄ and were subsequently filtered. Thefiltrate was cooled to 0° C. and HCl (4M in dioxane, 4.2 mL, 16.7 mmol)was added dropwise. The reaction was stirred at rt for 30 mins and thenconcentrated in vacuo to provide a white solid. The white solid wastriturated with Et₂O to provide 2d (528.5 mg, 79%) as a white solid.¹H-NMR (400 MHz, CD₃OD) δ 3.13 (s, 2H), 2.06 (s, 6H); LC/MS (APCI) m/z166.1 [C₇H₁₀F₃N+H]⁺.

A solution of 2d (0.327 g, 1.62 mmol) in DCM (8.11 mL) and sat. aq.NaHCO₃ (16.2 mL) at 0° C. was treated with acetic anhydride (0.828 g,8.11 mmol, 0.767 mL) and stirred at 0° C. After completion by LCMS (˜4h), the solution was extracted with DCM (4×30 mL). The combined organicswere washed with sat. NaHCO₃ (20 mL), brine (20 mL), dried (Na₂SO₄) andconcentrated under reduced pressure to afford the crude product as anoff-white solid that was further purified by flash chromatography (SiO₂,Hexanes/EtOAc) to afford 2 (0.304 g, 91%) as a white solid. ¹H NMR (400MHz, CDCl₃) δ 5.47 (br s, NH, 1H), 3.39 (d, J=6.06 Hz, 2H), 2.00 (s,3H), 1.89 (s, 6H); LC/MS (APCI) m/z 208.10 [C₉H₁₂F₃NO+H]⁺.

Example 3 Compound 3

A solution of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid(0.580 g, 3.22 mmol) in anhydrous tert-BuOH (16.1 mL) was treated withEt₃N (0.652 g, 6.44 mmol, 0.898 mL) and diphenylphosphoryl azide (1.06g, 3.86 mmol, 0.833 mL). The resulting solution was stirred at 30° C.under N₂ for 4 h, and then warmed to 90° C. and stirred overnight. Thesolution was concentrated under reduced pressure, diluted with H₂O (30mL) and extracted with EtOAc (3×20 mL). The combined organics were dried(MgSO₄) and concentrated to afford the crude product that was furtherpurified by flash chromatography (SiO₂, Hexanes/EtOAc) to provide 3-1(0.703 g, 87%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 4.95 (br s,NH, 1H), 2.22 (s, 6H), 1.45 (s, 9H); LC/MS (APCI) m/z 152.1[C₁₁H₁₆F₃NO₂—C₅H₉O₂+H]⁺.

A solution of 3-1 (0.703 g, 2.80 mmol) in EtOAc (7.0 mL) was treatedwith HCl (4.0 M in dioxane, 28.0 mmol, 7.0 mL), and the mixture wasstirred at rt overnight. After stirring overnight, white precipitateformed. The mixture was concentrated under reduced pressure. Theresulting white solid was triturated with diethyl ether and filtered toafford 3 (0.421 g, 80%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ9.19 (br s, NH, 3H), 2.26 (s, 6H); LC/MS (APCI) m/z 152.1 [C₆H₈F₃N+H]⁺.

Example 4 Compound 4

A solution of 3 (1.00 g, 5.33 mmol) in DCM (26.7 mL) and sat. aq. NaHCO₃(53.3 mL) at 0° C. was treated with acetic anhydride (2.72 g, 26.7 mmol,2.52 mL), and the mixture was stirred at 0° C. After completion(determined by LCMS, ˜3 h), the solution was extracted with DCM (4×20mL). The combined organics were dried (Na₂SO₄) and concentrated underreduced pressure to afford the crude product as an off-white solid.Purification by flash chromatography (SiO₂, Hexanes/EtOAc) to afford 4(0.868 g, 84%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 5.88 (br s,NH, 1H), 2.29 (s, 6H), 1.95 (s, 3H); LC/MS (APCI) m/z 194.1[C₈H₁₀F₃NO+H]⁺.

Example 5

Compound 5

A solution of methyllithium (5.30 mL, 8.48 mmol) was added dropwise to a0.311M solution of tricyclo[1.1.1.01,3]pentane (28.7 mL, 8.93 mmol) inEt₂O and methyl iodide (0.530 mL, 8.48 mmol) at −40° C. Once theaddition was complete, the solution was allowed to warm to rt and stirfor 24 h. The mixture was then cooled to −40° C., and MeOH (10 mL) wasadded. The resulting solution was poured into an ice-cold mixture of H₂O(50 mL) and pentane (50 mL). After separation of the layers, the organicphase was washed with H₂O (2×50 mL), dried (Na₂SO₄) and concentrated toa volume of ˜2 mL under reduced pressure at 0° C. The finalconcentration was determined by ¹H NMR and 5-1 (0.942 g, 51%) wasobtained as a colorless solution in Et₂O. ¹H NMR (400 MHz, CDCl₃) δ 2.21(s, 6H), 1.21 (s, 3H).

5-1 (0.940 g, 4.52 mmol) was dissolved in anhydrous Et₂O (15.1 mL) andcooled to −78° C. A solution of tert-butyllithium (1.7M in pentane,0.637 g, 9.94 mmol, 5.85 mL) was added dropwise, and the solution wasstirred at −78° C. for 1 h. After 1 h, CO₂ was bubbled through thesolution for 10 mins, and the reaction was allowed to warm to rt.Diethyl ether (10 mL) was added, and the mixture was extracted with H₂O(3×20 mL). The combined aqueous layers were acidified with 1M HCl, andthen extracted with Et₂O (3×20 mL). The combined organics were dried(MgSO₄) and concentrated under reduced pressure to afford 5-2 (0.501 g,88%) as a white solid, which was carried forward without furtherpurification. ¹H NMR (400 MHz, DMSO-d6) δ 12.11 (br s, COOH, 1H), 1.82(s, 6H), 1.14 (s, 3H).

5-2 (0.500 g, 3.96 mmol) was dissolved in tert-BuOH (19.8 mL). Et₃N(0.802 g, 7.93 mmol, 1.11 mL) and activated 3 Å molecular sieves wereadded followed by diphenylphosphoryl azide (1.025 mL, 4.76 mmol). Theresulting solution was stirred at 30° C. for 4 h, and then heated toreflux overnight. The solution was cooled to rt and then concentratedunder reduced pressure. The residual oil was diluted with EtOAc (20 mL)and H₂O (20 mL), and extracted with EtOAc (4×20 mL). The combinedorganics were dried (Na₂SO₄) and concentrated to afford the crudeproduct that was further purified by flash chromatography (SiO₂,Hexanes/EtOAc) to provide 5-3 (0.513 g, 66%) as a semi-pure white solid.¹H NMR (400 MHz, CDCl₃) δ 4.87 (br s, NH, 1H), 1.85 (s, 6H), 1.43 (s,9H), 1.21 (s, 3H); LC/MS (APCI) m/z 98.1 [C₁₁H₁₉NO₂—C₅H₉O₂+H]⁺.

To a solution of 5-3 (0.513 g, 2.60 mmol) in EtOAc (6.50 mL) was addedHCl (4 M in dioxane, 6.50 mL, 26.0 mmol). The resulting solution wasstirred at rt overnight. After stirring overnight, the mixture becamecloudy with partial precipitation of the product. The suspension wasconcentrated, and the residual solid was triturated with Et₂O (2×10 mL).The precipitate was collected by filtration, and the filter cake waswashed with Et₂O (20 mL). The white solid was dried under vacuum toafford 5 (0.219 g, 63%) as a white powder. ¹H NMR (400 MHz, DMSO-d6) δ8.69 (br s, NH, 3H), 1.84 (s, 6H), 1.22 (s, 3H); LC/MS (APCI) m/z 98.1[C₆H₁₁N+H]⁺.

Example 6 Compound 6

A solution of 5 (0.150 g, 1.12 mmol) in DCM (5.6 mL) and sat. aq. NaHCO₃(11.2 mL) at 0° C. was treated with acetic anhydride (0.573 g, 5.61mmol, 0.531 mL), and the mixture was stirred at 0° C. After 2 h, thesolution was extracted with DCM (4×10 mL), and the combined organicswere washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL), dried(MgSO₄) and concentrated under reduced pressure to afford the crudeproduct that was further purified by flash chromatography (SiO₂,Hexanes/EtOAc) to afford 6 (0.127 g, 81%) as a white solid. ¹H NMR (400MHz, CDCl₃) δ 5.78 (br s, NH, 1H), 1.93 (s, 6H), 1.91 (s, 3H), 1.21 (s,3H); LC/MS (APCI) m/z 140.1 [C₈H₁₃NO+H]⁺.

Example 7 Compound 7

A solution of MeLi (1.6 M, 10.1 mmol, 6.29 mL) was added dropwise to asolution of isopropyliodide (1.71 g, 10.1 mmol, 1.00 mL) and propellane(0.311 M in Et₂O, 0.700 g, 10.6 mmol, 34.1 mL) cooled to −40° C. Themixture was allowed to warm to rt and stirred for 24 h. The mixture wasthen cooled to −40° C. and MeOH (20 mL) was added. The resultingsolution was poured into an ice-cold mixture of H₂O (50 mL) and pentane(50 mL). After separation of the layers, the organic phase was washedwith H₂O (2×50 mL), dried (Na₂SO₄) and concentrated under reducedpressure at 0° C. to afford 7-1 (2.67 g, >99%) as a semi-pure colorlessoil that was used without further purification. ¹H NMR (400 MHz, CDCl₃)δ 2.15 (s, 6H), 1.78 (sep, J=6.8 Hz, 1H), 0.82 (d, J=6.8 Hz, 6H).

7-1 (2.50 g, 10.6 mmol) was dissolved in anhydrous Et₂O (35.3 mL) andcooled to −78° C. A solution of tert-BuLi (1.7M in pentane, 1.49 g, 23.3mmol, 13.7 mL) was added dropwise, and the solution was stirred at −78°C. for 1 h. After 1 h, CO₂ was bubbled through the solution for 10 mins,and the reaction was allowed to warm to rt. Et₂O (10 mL) was added, andthe mixture was extracted with H₂O (3×20 mL). The combined aqueouslayers were acidified with 1M HCl and then extracted with DCM (3×30 mL).The combined organics were dried (MgSO₄) and concentrated under reducedpressure to afford 7-2 (1.42 g, 87%) as an oily solid which was carriedforward without further purification. ¹H NMR (400 MHz, DMSO-d6) δ 12.18(br s, COOH, 1H), 1.73 (s, 6H), 1.64 (sep, J=6.8 Hz, 1H), 0.79 (d, J=6.8Hz, 6H).

A solution of 7-2 (1.42 g, 9.21 mmol) in anhydr. tert-BuOH (46.0 mL) wastreated with Et₃N (1.86 g, 18.4 mmol, 2.57 mL) and diphenylphosphorylazide (3.04 g, 11.1 mmol, 2.38 mL). The resulting solution was stirredat 30° C. under N₂. After 4 h, the solution was warmed to 90° C. andstirred overnight. The solution was concentrated under reduced pressureand then diluted with H₂O (30 mL). The solution was extracted with EtOAc(3×20 mL). The combined organics were dried (MgSO₄) and concentrated toafford the crude product that was further purified by flashchromatography (SiO₂, Hexanes/EtOAc) to provide 7-3 (1.42 g, 69%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 4.90 (br s, NH, 1H), 1.77 (s,6H), 1.75 (sep, J=6.8 Hz, 1H), 1.44 (s, 9H), 0.82 (d, J=6.8 Hz, 6H).

A solution of 7-3 (1.42 g, 6.30 mmol) in EtOAc (15.8 mL) was treatedwith HCl (4.0M in dioxane, 63.0 mmol, 15.8 mL), and the mixture wasstirred at rt overnight. The solution was concentrated under reducedpressure to afford the crude compound as an off-white solid. The solidwas triturated with Et₂O (3×5 mL) to afford 7 (0.858 g, 84%) as a whitepowder. ¹H NMR (400 MHz, DMSO-d6) δ 8.78 (br s, NH, 3H), 1.77 (sep,J=6.8 Hz, 1H), 1.75 (s, 6H), 0.81 (d, J=6.8 Hz, 6H); LC/MS (APCI) m/z126.1 [C₈H₁₅N+H]⁺.

Example 8 Compound 8

A solution of 7 (0.300 g, 1.86 mmol) in DCM (9.3 mL) and sat. aq. NaHCO₃(18.6 mL) at 0° C. was treated with acetic anhydride (0.947 g, 9.28mmol, 0.877 mL), and the mixture was stirred at 0° C. After 2 h, thesolution was extracted with DCM (4×20 mL). The combined organics werewashed with sat. aq. NaHCO₃ (20 mL) and brine (20 mL), dried (Na₂SO₄)and concentrated under reduced pressure to afford the crude product asan off-white solid that was further purified by flash chromatography(SiO₂, Hexanes/EtOAc) to afford 8 (0.289 g, 93%) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ 5.80 (br s, NH, 1H), 1.92 (s, 3H), 1.85 (s, 6H),1.76 (sep, J=6.8 Hz, 1H), 0.83 (d, J=6.8 Hz, 6H); LC/MS (APCI) m/z 168.1[C₁₀H₁₇NO+H]⁺.

Example 9 Compound 9

A solution of 9-1 (0.300 g, 2.51 mmol) in DCM (8.36 mL) at 0° C. wastreated with Et₃N (0.635 g, 6.27 mmol, 0.874 mL) and trifluoroaceticanhydride (0.632 g, 3.01 mmol, 0.425 mL). The mixture was allowed towarm to rt and stir overnight. The mixture was extracted with DCM (4×5mL). The combined organic layers were washed with 1M HCl (5 mL), H₂O (5mL), sat. NaHCO₃ (5 mL) and then brine (5 mL). The combined organiclayers were dried (Na₂SO₄) and concentrated under reduced pressure toprovide the crude product that was further purified by flashchromatography (SiO₂, Hexanes/EtOAc) to afford 9 (0.232 g, 52%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 6.60 (br s, NH, 1H), 2.54 (s,1H), 2.17 (s, 6H); LC/MS (APCI) m/z 180.1 [C₇H₈F₃NO+H]⁺.

Example 10 Compound 10

A solution of 10-1 (0.300 g, 1.71 mmol) in DCM (5.69 mL) at 0° C. wastreated with Et₃N (0.432 g, 4.27 mmol, 0.595 mL) and trifluoroaceticanhydride (0.430 g, 2.05 mmol, 0.289 mL). The mixture was allowed towarm to rt. After 3 h, the mixture was extracted with DCM (4×5 mL). Thecombined organic layers were washed with 1M HCl (5 mL), H₂O (5 mL), sat.NaHCO₃ (5 mL) and then brine (5 mL). The combined organic layers weredried (Na₂SO₄) and concentrated under reduced pressure to provide thecrude product that was further purified by flash chromatography (SiO₂,Hexanes/EtOAc) to afford 10 (0.375 g, 93%) as a white solid. ¹H NMR (400MHz, CDCl₃) δ 6.55 (br s, NH, 1H), 1.94 (s, 6H), 0.88 (s, 9H); LC/MS(APCI) m/z 234.1 [C₁₁H₁₆F₃NO—H]⁺.

Example 11 Compound 11

A solution of 10-1 (0.200 g, 1.14 mmol) in DCM (5.69 mL) and sat. aq.NaHCO₃ (11.4 mL) at 0° C. was treated with pivaloyl chloride (0.690 g,5.69 mmol, 0.635 mL). The mixture was stirred at rt for 2 h. The mixturewas then extracted with DCM (4×5 mL). The combined organic layers werewashed with 1M HCl (5 mL), H₂O (5 mL), sat. NaHCO₃ (5 mL) and then brine(5 mL). The combined organic layers were dried (Na₂SO₄) and concentratedunder reduced pressure to provide the crude product that was furtherpurified by flash chromatography (SiO₂, Hexanes/EtOAc) to afford 11(0.224 g, 88%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 5.91 (br s,NH, 1H), 1.85 (s, 6H), 1.17 (s, 9H), 0.86 (s, 9H); LC/MS (APCI) m/z224.2 [C₁₄H₂₅NO+H]⁺.

Example 12 Compound 12

A solution of 9-1 (0.300 g, 2.51 mmol) in DCM (12.5 mL) and sat. aq.NaHCO₃ (25.1 mL) at 0° C. was treated with pivaloyl chloride (1.51 g,12.5 mmol, 1.4 mL), and the mixture was stirred at rt. After 2 h, themixture was extracted with DCM (4×10 mL). The combined organic layerswere washed with 1M HCl (10 mL), H₂O (10 mL), sat. NaHCO₃ (10 mL) andthen brine (10 mL). The combined organic layers were dried (Na₂SO₄) andconcentrated under reduced pressure to provide the crude product thatwas further purified by flash chromatography (SiO₂, Hexanes/EtOAc) toafford 12 (0.220 g, 52%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ5.95 (br s, NH, 1H), 2.44 (s, 1H), 2.08 (s, 6H), 1.17 (s, 9H); LC/MS(APCI) m/z 168.1 [C₁₀H₁₇NO+H]⁺.

Example 13 Compound 13

To a suspension of NaH (60% in mineral oil, 0.134 g, 3.34 mmol) inanhydrous DMF (0.62 mL) at 0° C. was added a solution of 13-1 (0.400 g,1.67 mmol) in DMF (3.34 mL). The mixture was stirred for 5 mins followedby the addition of MeI (0.710 g, 5.01 mmol, 0.312 mL). The resultingsolution was allowed to warm to rt. After 2 h, the reaction was quenchedby the addition of water (1 mL). The mixture was diluted with EtOAc (20mL) and H₂O (50 mL), and extracted with EtOAc (3×20 mL). The combinedorganics were dried (Na₂SO₄) and concentrated under reduced pressure toafford an oil that was further purified by flash chromatography (SiO₂,0-50% EtOAc/Hexanes) to afford 13-2 (0.394 g, 93%) as a colorless oil.¹H NMR (400 MHz, CDCl₃) δ 2.78 (s, 3H), 1.80 (s, 6H), 1.46 (s, 9H), 0.86(s, 9H); LC/MS (APCI) m/z 154.2 [C₁₅H₂₇NO₂—C₅H₉O₂+H]⁺.

A solution of 13-2 (0.394 g, 1.55 mmol) in EtOAc (3.88 mL) was treatedwith HCl (4.0M in dioxane, 15.5 mmol, 3.9 mL), and the mixture wasstirred at rt overnight. The solution was concentrated under reducedpressure to afford the crude compound as a white solid. The solid wasfiltered and washed with Et₂O (3×10 mL) to afford 13 (0.294 g, >99%) asa white solid. ¹H NMR (400 MHz, DMSO-d6) δ 9.43 (br s, NH, 3H), 2.46 (s,3H), 1.75 (s, 6H), 0.86 (s, 9H).

Example 14 Compound 14

A solution of 13 (0.294 g, 1.55 mmol) in DCM (7.75 mL) and sat. aq.NaHCO₃ (15.5 mL) at 0° C. was treated with acetic anhydride (0.791 g,7.75 mmol, 0.732 mL), and the mixture was stirred at 0° C. After 1.5 h,the solution was extracted with DCM (4×20 mL). The combined organicswere washed with sat. aq. NaHCO₃ (20 mL) and brine (20 mL), dried(Na₂SO₄) and concentrated under reduced pressure to afford the crudeproduct as an off-white solid that was further purified by flashchromatography (SiO₂, Hexanes/EtOAc) to afford 14 (0.272 g, 90%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 2.87 (s, 3H), 2.12 (s, 3H), 1.91(s, 6H), 0.88 (s, 9H); LC/MS (APCI) m/z 196.2 [C₁₂H₂₁NO+H]⁺.

Example 15 Compound 15

To a suspension of 15-1 (0.800 g, 6.69 mmol) and NaH (60% in mineraloil, 0.562 g, 14.1 mmol) in THF (33.4 mL) at 0° C. was added Boc₂O (1.61g, 7.36 mmol, 1.71 mL). The resulting solution was allowed to warm to rtand stir for 24 h. The solution was then cooled to 0° C. and H₂O (2 mL)was slowly added. The mixture was further diluted with H₂O (20 mL) andextracted with EtOAc (4×20 mL). The combined organics were dried(Na₂SO₄) and concentrated under reduced pressure to provide a semi-solidthat was further purified by flash chromatography (SiO₂, Hexanes/EtOAc)to afford 15-2 (0.708 g, 58%) as a white solid. ¹H NMR (400 MHz, CDCl₃)δ 4.91 (br s, NH, 1H), 2.39 (s, 1H), 2.00 (s, 6H), 1.44 (s, 9H); LC/MS(APCI) m/z 84.1 [C₁₀H₁₇NO₂— C₅H₉O₂+H]⁺.

To a suspension of NaH (60% in mineral oil, 0.0921 g, 3.84 mmol) inanhydrous DMF (0.710 mL) at 0° C. was added a solution of 15-2 (0.352 g,1.92 mmol) in DMF (3.84 mL). The mixture was stirred for 5 mins and thenMeI (0.817 g, 5.76 mmol, 0.358 mL) was added. The resulting solution wasallowed to warm to rt and stir for 4 h. The solution was then cooled to0° C., and H₂O (2 mL) was slowly added. The mixture was diluted with H₂O(20 mL) and extracted with EtOAc (3×20 mL). The combined organics weredried (Na₂SO₄) and concentrated to afford a semi-pure oil that wasfurther purified by flash chromatography (SiO₂, Hexanes/EtOAc) to afford15-3 (0.248 g, 65%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 2.78 (s,3H), 2.36 (s, 1H), 2.02 (s, 6H), 1.46 (s, 9H); LC/MS (APCI) m/z 98.1[C₁₁H₁₉NO₂—C₅H₉O₂+H]⁺.

A solution of 15-3 (0.247 g, 1.25 mmol) in EtOAc (3.13 mL) was treatedwith HCl (4.0M in dioxane, 12.5 mmol, 3.13 mL), and the mixture wasstirred overnight at rt. The solution was concentrated under reducedpressure to afford the crude compound as an off-white solid. The solidwas triturated with Et₂O (3×5 mL) and filtered to afford 15 (0.143 g,86%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 9.60 (br s, NH, 2H),2.66 (s, 1H), 2.44 (s, 3H), 1.97 (s, 6H); LC/MS (APCI) m/z 98.1[C₆H₁₁N+H]⁺.

Example 16 Compound 16

A solution of 16-1 ((prepared according to Eur. J. Org. Chem. 2004,493-498), 0.400 g, 1.67 mmol) in THF (6.2 mL) was cooled to 0° C. andtreated with MgBrCH₃ (4.0M in Et₂O, 2.1 mL, 6.22 mmol). After 15 mins,the reaction was warmed to rt. After 4 h, the reaction was cooled to 0°C. and quenched with sat. aq. NH₄Cl solution (5 mL). After warming tort, the reaction was diluted with EtOAc and H₂O. The organic layer wasseparated. The aqueous layer was saturated with NaCl(s) and thenextracted with EtOAc (3×20 mL). The combined organics were dried(Na₂SO₄) and concentrated under reduced pressure to afford an oil thatwas further purified by flash chromatography (SiO₂, 0-100%EtOAc/Hexanes) to afford 16-2 (0.190 g, 63%) as a colorless oil. ¹H NMR(400 MHz, CDCl₃) δ 1.93 (s, 6H), 1.47 (s, 9H), 1.21 (s, 6H).

To a solution of 16-2 (0.200 g, 0.829 mmol) in THF (4.14 mL) at 0° C.was added NaH (60% in mineral oil, 0.0497 g, 1.243 mmol). The mixturewas stirred for 10 mins, followed by the addition of MeI (0.124 g, 0.870mmol, 54.2 L). The resulting solution was allowed to warm to rt, andthen stirred overnight. The solution was cooled to 0° C., and H₂O (2 mL)was slowly added. The mixture was diluted with H₂O (5 mL) and extractedwith EtOAc (3×10 mL). The combined organics were dried (Na₂SO₄) andconcentrated to an oil that was further purified by flash chromatography(SiO₂, Hexanes/EtOAc) to afford 16-3 (0.120 g, 57%) as a clear colorlessoil. ¹H NMR (400 MHz, DMSO-d6) δ 4.15 (s, 1H), 2.69 (s, 3H), 1.80 (s,6H), 1.39 (s, 9H), 1.04 (s, 6H); LC/MS (APCI) m/z 156.10[C₁₄H₂₅NO₃—C₅H₉O₂+H]⁺.

A solution of 16-3 (120 mg, 0.470 mmol) in DCM (4.7 mL) was cooled to 0°C. and treated with TFA (1.2 mL). The reaction was warmed to rt andstirred for 3 h. The reaction was then concentrated in vacuo to providea clear colorless oil. The crude mixture was redissolved in CH₂Cl₂ andre-concentrated (2×) to remove residual TFA. DCM (3 mL) was added to thecrude product. The solution was cooled to 0° C., and then treated withHCl (4.0M in dioxane, 8.0 mmol, 2.00 mL). The mixture was stirred for 30mins at rt. The solution was concentrated under reduced pressure toafford the crude compound as an off-white solid. The solid wastriturated with Et₂O and filtered to provide 16 (56.5 mg, 63%) as awhite solid. ¹H NMR (400 Mhz, DMSO-d6) δ 9.41 (br s, 2H), 4.38 (s, 1H),2.46 (s, 3H), 1.79 (s, 6H), 1.06 (s, 6H); LC/MS (APCI) m/z 156.10[C₉H₁₇NO+H]⁺.

Example 17 Compound 17

A solution of 16-2 (190 mg, 0.787 mmol) in DCM (8 mL) was cooled to 0°C. and treated with TFA (2 mL). The mixture was warmed to rt and stirredfor 2 h. The mixture was concentrated in vacuo. The crude mixture wasthen dissolved in CH₂Cl₂ and re-concentrated (2×) to remove residualTFA. The crude reaction was then triturated with EtOAc, followed byEt₂O. The mixture was filtered to afford 17 (185.7 mg, 92%) as a whitesolid. ¹H NMR (400 Mhz, CD₃OD): δ 1.97 (s, 6H), 1.19 (s, 6H); LC/MS(APCI) m/z 142.10 [C₈H₁₅NO+H]⁺.

Example 18 Compound 18

A solution of 17 (185.7 mg, 0.728 mmol) in DCM (3.7 mL) was cooled to 0°C. and treated with triethylamine (355 μL, 2.55 mmol) and aceticanhydride (103 μL, 1.09 mmol). The reaction was warmed graduallyovernight. After 16 h, water was added, and the reaction solution wasextracted with DCM (3×10 mL). The combined organics were dried (Na₂SO₄)and concentrated under reduced pressure to afford the crude product asan off-white solid that was further purified by flash chromatography(SiO₂, CH₂Cl₂/MeOH) to afford 18 (0.107 g, 80%) as a white solid. ¹H NMR(400 Mhz, DMSO-d6): δ 8.26 (s, 1H), 4.09 (s, 1H), 1.76 (s, 6H), 1.73 (s,3H), 1.03 (s, 6H); LC/MS (APCI) m/z 184.10 [C₁₀H₁₇NO₂+H]⁺.

Example 19 Compound 19

A solution of tert-butyl(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (0.200 g, 0.796mmol) in DMF (1.990 mL) at 0° C. was treated with NaH (0.038 g, 1.592mmol). The suspension was stirred for 5 mins followed by the addition ofiodomethane (0.149 mL, 2.388 mmol). The solution was allowed to warm tort and followed by LCMS. Once complete (2 h), the solution was cooled to0° C. and quenched with H₂O (1 mL). The mixture was diluted with H₂O (10mL) and extracted with EtOAc (4×10 mL). The combined organics were dried(Na₂SO₄) and concentrated to give the crude product which was furtherpurified by flash chromatography (SiO₂, Hexanes/EtOAc) to provide 19-1(126 mg, 60%) as a viscous colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 2.80(s, 3H), 2.24 (s, 6H), 1.47 (s, 9H); LC/MS (APCI) m/z 166.10[C₁₂H₁₈F₃NO₂—C₅H₉O₂+H+].

A solution of tert-butylmethyl(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (0.125 g,0.471 mmol) in ethyl acetate (1.178 mL) was treated with HCl (4M indioxane) (1.178 mL, 4.71 mmol). The solution was stirred at rtovernight. The suspension was concentrated, and then triturated withEt₂O (2×10 mL). The precipitate was collected by filtration and thefilter cake was washed with Et₂O (20 mL). The white solid was driedunder vacuum to afford 19 (80.4 mg, 85%) as a white powder. ¹H NMR (400MHz, DMSO-d₆) δ 10.12 (br s, NH 2H), 2.56 (s, 3H), 2.29 (s, 6H); LC/MS(APCI) m/z 166.10 [C₇H₁₀F₃N+H+].

Example 20 Compound 20

A solution of N-methylbicyclo[1.1.1]pentan-1-amine hydrochloride (0.160g, 1.20 mmol) in DCM (5.99 mL) and sat. aq. NaHCO₃ (12.0 mL) at 0° C.was treated with acetic anhydride (0.610 g, 5.99 mmol, 0.566 mL). Thesolution was stirred at 0° C. After completion by LCMS (˜4 h), thesolution was extracted with DCM (4×20 mL). The combined organics werewashed with sat. aq. NaHCO₃ (20 mL) and brine (20 mL), dried (MgSO₄) andconcentrated under reduced pressure to afford the crude product as anoff-white solid. The crude product was further purified by flashchromatography (SiO₂, Hexanes/EtOAc) to afford 20 (0.128 g, 76%) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 2.86 (s, 3H), 2.46 (s, 1H),2.12 (s, 9H); LC/MS (APCI) m/z 140.10 [C₈H₁₃NO+H]⁺.

Example 21 Compound 21

A solution of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid(0.300 g, 1.67 mmol) in DCM (8.33 mL) at 0° C. was treated with oxalylchloride (0.292 mL, 3.33 mmol) and DMF (couple of drops). Bubbling beganimmediately, and the solution became homogenous. The solution was warmedto rt and stirred for 2.5 h. The solvent was removed under high vacuum.The residue was dissolved in anhydrous acetonitrile (8.33 mL) and THF(8.33 mL). Et₃N (0.557 mL, 4.00 mmol) was added, and after stirring for˜5 mins, the mixture was cooled to 0° C. A 2M solution ofTMS-diazomethane (3.33 mL, 6.66 mmol) in ether was added. The solutionwas warmed to rt and stirred for 5.5 h. Once complete, the reaction wasquenched by the addition of 10% citric acid (˜10 mL). The majority ofthe organic layer was removed via rotovap. The mixture was diluted withEtOAc (150 mL) washed with 10% citric acid (20 mL), H₂O (20 mL), sat.aq. NaHCO₃ (20 mL), and brine (20 mL). The organic layer was dried(Na₂SO₄) and concentrated to provide the crude product which was furtherpurified by flash chromatography (SiO₂, Hexanes/EtOAc) to provide 21-1(0.190 g, 56%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 5.31 (s,1H), 2.20 (s, 6H).

A solution of2-diazo-1-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)ethanone (0.190g, 0.930 mmol) in THF (27 mL) and water (9.30 mL) was treated with a THFsolution (10 mL) of silver(I) benzoate (0.043 g, 0.186 mmol) and Et₃N(0.518 mL, 3.72 mmol). The resulting dark solution was sonicated at rtfor 30 mins while protected from light. The mixture was concentrated to˜30% of its original volume. The solution was acidified with 1N HCl,diluted with H₂O (30 mL) and extracted with EtOAc (4×30 mL). Thecombined organics were dried (Na₂SO₄) and concentrated to afford thecrude product which was partially purified by flash chromatography(SiO₂, Hexanes/EtOAc, 1% AcOH) to give 21-2 (0.125 g, 69%) as a lightyellow oil which was used without further purification. ¹H NMR (400 MHz,CDCl₃) δ 2.63 (s, 2H), 2.02 (s, 6H).

A solution of 2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)aceticacid (0.125 g, 0.644 mmol) in DCM (3.22 mL) was cooled to 0° C. and DMF(2 drops) were added. Oxalyl chloride (0.124 mL, 1.416 mmol) wasinjected. The solution was allowed to warm to rt and stir for 2.5 h. Thesolution was then cooled to 0° C. Ammonium hydroxide (4.43 mL, 32.2mmol) was added in one portion with rapid stirring and a whiteprecipitate formed. The reaction was stirred overnight, diluted with H₂O(5 mL) and extracted with EtOAc (5×15 mL). The combined organics weredried (Na₂SO₄) and concentrated to provide 21-3 (102 mg, 82%) as a whitesolid, which was used without further purification. ¹H NMR (400 MHz,DMSO-d₆) δ 7.27 (br s, NH, 1H), 6.79 (br s, NH, 1H), 2.31 (s, 2H), 1.89(s, 6H); LC/MS (APCI) m/z 194.10 [C₈H₁₀F₃NO+H]⁺.

A solution of 2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetamide(0.041 g, 0.212 mmol) in anhydrous THF (1.061 mL) was treated with a1.0M solution of borane tetrahydrofuran complex (0.425 mL, 0.425 mmol)in THF. The solution was heated to 67° C. and stirred until complete asdetermined by LCMS. Once complete, the reaction was cooled to rt andquenched by the addition of 1M HCl in H₂O. The solution was stirred for1 h, concentrated and used without further purification.

A solution of crude2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)ethanamine,hydrochloride (0.038 g, 0.176 mmol) in DCM (1.762 mL) was treated withEt₃N (0.074 mL, 0.529 mmol) and Boc-anhydride (0.049 mL, 0.211 mmol).The solution was stirred at rt for 2 h, diluted with 10% citric acid (2mL) and extracted with DCM (4×3 mL). The combined organic layers weredried (Na₂SO₄) and concentrated to provide the crude product, which wasfurther purified by flash chromatography (SiO₂, Hexanes/EtOAc) toprovide 21-4 (19.1 mg, 39%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ4.45 (br s, NH, 1H), 3.14 (m, 2H), 1.87 (s, 6H), 1.70 (t, J=7.21, 2H),1.44 (s, 9H); LC/MS (APCI) m/z 180.10 [C₁₃H₂₀F₃NO₂—C₅H₉O₂+H]⁺.

A solution of tert-butyl(2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)ethyl)carbamate (0.0191g, 0.068 mmol) in ethyl acetate (0.684 mL) was treated with a 2Msolution of HCl (0.684 mL, 1.37 mmol) in Et₂O. The solution was stirredovernight. Additional HCl in ether (10 eq.) was added, and the reactionwas stirred for 48 h. Once complete, the mixture was concentrated, andthe resulting white solid was triturated with Et₂O (3×1 mL) to provide21 (10.3 mg, 70%) as a white powder. ¹H NMR (400 MHz, DMSO-d₆) δ 7.82(br s, NH, 3H), 2.74 (m, 2H), 1.90 (s, 6H), 1.80 (m, 2H); LC/MS (APCI)m/z 180.10 [C₈H₁₂F₃N+H]⁺.

Example 22 Compound 22

A solution of 1-iodo-3-(trifluoromethyl)bicyclo[1.1.1]pentane (0.137 g,0.523 mmol) in toluene (2.61 mL) was treated with acrylonitrile (0.069mL, 1.046 mmol), AIBN (4.29 mg, 0.026 mmol), and nBu₃SnH (0.209 mL,0.784 mmol). The solution was placed in a pre-heated plate at 80° C. andstirred for 4 h. The mixture was concentrated and purified by flashchromatography (SiO₂, Hexanes/EtOAc) to provide 22-1 (80.9 mg 82%) as asemi-pure yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 2.34 (t, J=7.1 Hz, 2H),1.95 (s, 6H),

A solution of3-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)propanenitrile (0.04 g,0.211 mmol) in anhydrous MeOH (1.626 mL) was cooled to 0° C. Thesolution was treated with Boc-anhydride (0.098 mL, 0.423 mmol) and thenNiCl_(2.)6H₂O (5.03 mg, 0.021 mmol). NaBH₄ (0.056 g, 1.480 mmol) wasadded. Once the addition was complete, the mixture was allowed to warmto rt and stirred. Once complete, the reaction was concentrated andfurther purified by reverse phase ISCO (C18, H₂O/MeCN each w/ 0.1%formic acid) to provide 22-2 (12.3 mg, 20%) as an off-white solid. ¹HNMR (400 MHz, CDCl₃) δ 4.51 (br s, NH, 1H), 3.11 (m, 2H), 1.81 (s, 6H),1.54-1.48 (m, 4H), 1.44 (s, 9H); LC/MS (APCI) m/z 194.10[C₁₄H₂₂F₃NO₂—C₈H₉O₂+H]⁺.

A solution of tert-butyl(3-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)propyl)carbamate (0.019g, 0.065 mmol) in ethyl acetate (0.648 mL) was treated with a 2Msolution of HCl (0.648 mL, 1.295 mmol) in diethyl ether. The solutionwas stirred overnight. Once complete, the suspension was concentrated todryness, and the resulting white solid was further triturated with Et₂Oto provide 22 (12.8 mg, 86%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 7.76 (br s, NH, 3H), 2.76 (m, 2H), 1.84 (s, 6H), 1.80 (m, 2H), 1.53(m, 4H); LC/MS (APCI) m/z 194.10 [C₉H₁₄F₃N+H]⁺.

Example 23 Compound 23

A solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid(0.500 g, 2.94 mmol) in DCM (14.69 mL, 2.94 mmol) was treated with DMF(2 drops) followed by oxalyl chloride (0.566 mL, 6.46 mmol). Thesolution was stirred at rt for 2.5 h. The solvent was removed underreduced pressure, and the crude acid chloride was dried under vacuum.The crude acid chloride was re-dissolved in benzene (5.88 mL, 2.94 mmol)and dimethyl disulfide (1.306 mL, 14.69 mmol) was added while thesolution was protected from light. In a separate flask,2-pyridinethiol-1-oxide sodium salt (0.482 g, 3.23 mmol) in benzene(5.88 mL, 2.94 mmol) was heated to 50° C. The solution containing theacid chloride was added dropwise to the 2-pyridinethiol-1-oxide sodiumsalt (0.482 g, 3.23 mmol) solution while being irradiated with a halogenwork lamp. Once the addition was complete, the mixture was irradiatedfor 1.5 h or until the reaction was complete as determined by LCMS. Thereaction was quenched with sat. aq. NaHCO₃ (˜15 mL), and further dilutedwith H₂O (10 mL). The solution was extracted with EtOAc (4×20 mL). Thecombined organics were dried (Na₂SO₄) and concentrated to afford a darkorange oil which was further purified by flash chromatography (SiO₂,Hexanes/EtOAc) to provide 23-1 (0.263 g, 52%) as a colorless oil alongwith the symmetrical thiohydroxamate ester 23-A. ¹H NMR (400 MHz, CDCl₃)δ 3.68 (s, 3H), 2.18 (s, H), 2.08 (s, 3H).

To a solution of methyl3-(methylthio)bicyclo[1.1.1]pentane-1-carboxylate (0.263 g, 1.527 mmol)in MeOH (3.82 mL) is added Oxone® (2.82 g, 4.58 mmol) in water (3.82 mL)at 0° C. The solution is allowed to warm to rt and stirred. Oncecomplete as determined by ¹H NMR and TLC (2.5 h), the mixture wasdiluted with H₂O (30 mL) and extracted with EtOAc (4×20 mL). Thecombined organics were dried (Na₂SO₄) and concentrated to afford a whitesolid which was re-dissolved in EtOAc and filtered through a 0.45 μmfilter. Concentration of the solution provided 23-2 (0.280 g, 90%) as awhite solid after high vacuum, which required no further purification.¹H NMR (400 MHz, CDCl₃) δ 3.73 (s, 3H), 2.86 (s, 3H), 2.48 (s, 6H).

A solution of methyl3-(methylsulfonyl)bicyclo[1.1.1]pentane-1-carboxylate (0.279 g, 1.366mmol) in THF (6.83 mL) was treated with an aqueous 2M solution of LiOH(3.01 mL, 3.01 mmol), and the solution was stirred at rt overnight. Themixture was then diluted with Et₂O (5 mL) and extracted with H₂O (4×10mL). The combined aqueous layers were acidified (1N HCl) and extractedwith EtOAc (4×10 mL). The combined organics were dried (Na₂SO₄) andconcentrated to afford 23-3 (0.202 g, 78%) as a white powder, which wasused without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 12.90 (brs, COOH, 1H), 2.96 (s, 3H), 2.33 (s, 6H).

To a suspension of 3-(methylsulfonyl)bicyclo[1.1.1]pentane-1-carboxylicacid (0.202 g, 1.062 mmol) in toluene (5.31 mL) were added crushed 3 Åmol sieves, Et₃N (0.296 mL, 2.124 mmol), tert-butanol (0.122 mL, 1.274mmol) and phosphorazidic acid diphenyl ester (0.275 mL, 1.274 mmol). Thesolution was stirred at rt for 4 h, and then heated to 90° C. Thesolution was stirred at overnight. The mixture was cooled to rt andfiltered through a 0.45 μm filter. The filter was washed with EtOAc, andthe filtrate was diluted with H₂O (5 mL) and extracted with EtOAc (4×10mL). The combined organics were dried (Na₂SO₄) and concentrated toafford the crude product which was further purified by flashchromatography (SiO₂, Hexanes/EtOAc) to provide 23-4 (0.173 g, 63%)which solidified upon standing. ¹H NMR (400 MHz, CDCl₃) δ 5.01 (br s,NH, 1H), 2.87 (s, 3H), 2.47 (s, 6H), 1.45 (s, 9H); LC/MS (APCI) m/z162.0 [C₁₁H₁₉NO₄S—C₅H₉O₂+H]⁺.

A solution of tert-butyl(3-(methylsulfonyl)bicyclo[1.1.1]pentan-1-yl)carbamate (0.173 g, 0.662mmol) in ethyl acetate (1.655 mL) was treated with a 4M solution of HCl(0.827 mL, 3.31 mmol) in dioxane. The solution stirred at rt overnight.Once complete, the mixture was concentrated to provide the desiredproduct which was further triturated with Et₂O to afford 23 (97.3 mg,74%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.18 (br s, NH, 3H),3.04 (s, 3H), 2.38 (s, 6H); LC/MS (APCI) m/z 162.0[C₁₁H₁₉NO₄S—C₈H₉O₂+H]⁺.

Example 24 Compound 24

To a solution of propellane (0.36M in Et₂O, 10 mL, 3.57 mmol) at 0° C.was added phenylmagnesium bromide (3M in Et₂O, 1.190 mL, 3.57 mmol). Thecooling bath was removed, and the reaction vessel was sealed and stirredat rt for 3.5 d. The reaction was then cooled to 0° C. and treated witha solution of N-fluorobenzenesulfonimide (NFSI) (1.35 g, 4.3 mmol) inTHF (5 mL). Additional THF (5 mL) was added to the mixture to aid insolubility, and the reaction was stirred at rt. After 1 h, H₂O wasadded, and the mixture was extracted with pentane (×5). The combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated invacuo. The product was purified by flash chromatography (SiO₂, heptane)to afford 24-1 (113.4 mg, 20%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃)δ 7.35-7.10 (m, 5H), 2.35 (d, J=2.5 Hz, 6H).

A solution of 1-fluoro-3-phenylbicyclo[1.1.1]pentane (113.4 mg, 0.699mmol) in DCM (1.165 mL):acetonitrile (5.83 mL) was treated with sodiumperiodate (2.24 g, 10.5 mmol) in water (9 mL) followed by Ruthenium(III)chloride trihydrate (54.8 mg, 0.210 mmol). The reaction was sealed andreacted overnight at rt. The solution was diluted with H₂O and extractedwith CH₂Cl₂ (3×). The combined organics were dried over Na₂SO₄,filtered, and concentrated in vacuo to afford the crude product as ayellow oil. The product was purified by flash chromatography (SiO₂,hexanes/EtOAc) to afford 24-2 (34.2 mg, 38%) as a white solid. ¹H-NMR(400 MHz, DMSO-d₆) δ 12.75 (s, 1H), 2.29 (d, J=2.6 Hz, 6H).

A solution of 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (34 mg,0.261 mmol in anhydrous tBuOH (1.3 mL) was treated with Et₃N (72.8 μL,0.523 mmol) and DPPA (67.6 μL, 0.314 mmol). The solution was stirred at30° C. under N₂. After 4 h, the solution was warmed to 90° C. andstirred overnight. The solution was concentrated via rotovap, andadsorbed onto silica using DCM. The crude product was purified by flashchromatography (SiO₂, Hexanes/EtOAc) to afford 24-3 (40 mg, 76%) as awhite solid. ADPPA side product co-eluted with the product, and wasseparated out in the next step. ¹H-NMR (400 MHz, CDCl₃) δ 2.38 (s, 6H),1.45 (s, 9H); LC/MS (APCI) m/z 102.1 [C₁₀H₁₆FNO₂—C₈H₉O₂+H]⁺.

A solution of tert-butyl (3-fluorobicyclo[1.1.1]pentan-1-yl)carbamate(0.04 g, 0.199 mmol) in EtOAc (1.0 mL) was treated with HCl (4.0M indioxane, 0.994 mmol, 0.25 mL). The mixture was stirred rt overnight. Thesolution was concentrated under reduced pressure to afford the crudecompound as an off-white solid. The solid was triturated with Et₂O toafford 24 (13.6 mg, 50%) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ8.83 (br s, NH, 3H), 2.34 (d, 6H); LC/MS (APCI) m/z 102.1 [C₅H₈FN+H]⁺.

Example 25 Compound 25

A solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid(700 mg, 4.11 mmol) in Et₂O (16.5 mL) at 0° C. was treated with DMF(32.0 μL, 0.411 mmol) and oxalyl chloride (792 μL, 9.05 mmol). Themixture was warmed to rt. After 70 mins, the solvent was removed invacuo, and the crude product was dissolved in CCl₄ (5 mL). To a separateflask with stir bar was added sodium 2-thioxopyridin-1(2H)-olate (736mg, 4.94 mmol), followed by carbon tetrachloride (21 mL). Theheterogeneous solution was heated to reflux, and the solution of crudeacid chloride in CCl₄ was added dropwise over 15 mins under irradiationusing a halogen work lamp. After 90 mins, the reaction was cooled to rt.The reaction was added to 1M HCl (aq., 50 mL). The organic layer wasremoved, and the aqueous layer was washed with DCM (3×30 mL). Thecombined organic layers were washed with sat. aq. NaHCO₃, dried(Na₂SO₄), filtered and concentrated in vacuo to provide the crude 25-1as a yellow oil which was used directly for the next reaction withoutfurther purification. ¹H-NMR (400 MHz, CDCl₃) δ 3.69 (s, 3H), 2.42 (s,6H).

A solution of crude methyl 3-chlorobicyclo[1.1.1]pentane-1-carboxylate(500 mg, 3.11 mmol) in THF (8.3 mL):H₂O (2.1 mL) was treated withlithium hydroxide monohydrate (653 mg, 15.57 mmol) at rt. After 3 h, THFwas removed in vacuo, and H₂O and Et₂O were added. The organic phase wasseparated, and the aqueous layer was extracted with Et₂O. The aqueouslayer was acidified with 3M HCl (aq.), and then extracted with DCM (3×30mL). The combined organic layers (following acidification) were dried(Na₂SO₄), filtered and concentrated under reduced pressure to afford25-2 (108.8 mg, 24%) as an off-white solid. ¹H-NMR (400 MHz, CDCl₃) δ2.45 (s, 6H).

25-2 (0.108 g, 0.737 mmol) was dissolved in tert-BuOH (3.7 mL). Et₃N(0.149 g, 1.47 mmol, 0.21 mL) and activated 3 Å molecular sieves wereadded followed by diphenylphosphoryl azide (191 μL, 0.884 mmol). Thesolution was stirred at 30° C. for 4 h, and then heated to refluxovernight. The solution was cooled to rt and then concentrated underreduced pressure. The residual oil was diluted with EtOAc (20 mL) andH₂O (20 mL), and extracted with EtOAc (3×20 mL). The combined organicswere dried (Na₂SO₄) and concentrated to afford the crude product thatwas further purified by flash chromatography (SiO₂, Hexanes/EtOAc) toprovide 25-3 (67.6 mg, 42%) as a semi-pure white solid. ¹H NMR (400 MHz,CDCl₃) δ 2.36 (s, 6H), 1.44 (s, 9H); LC/MS (APCI) m/z 118.0[C₁₀H₁₉ClNO₂—C₈H₉O₂+H]⁺.

To a solution of 25-3 (67.6 mg, 0.311 mmol) in EtOAc (1.55 mL) was addedHCl (4 M in dioxane, 0.388 mL, 1.55 mmol). The solution was stirred atrt overnight. After stirring overnight, the mixture became cloudy withpartial precipitation of the product. The suspension was concentrated,and the residual solid was triturated with Et₂O (2×10 mL). Theprecipitate was collected by filtration, and the filter cake was washedwith Et₂O (20 mL). The white solid was dried under vacuum to afford 25(36.0 mg, 75%) as a white powder. ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (brs, NH, 3H), 2.38 (s, 6H); LC/MS (APCI) m/z 118.0 [C₅H₈ClN+H]⁺.

Example 26 Compound 26

To a solution of propellane (0.305M in Et₂O, 62.0 mL, 18.9 mmol) wasadded p-tolylmagnesium bromide (0.5M in Et₂O, 37.8 mL, 18.9 mmol). Thereaction flask was sealed and stirred at rt. After 4 d, the mixture wascooled to 0° C. and dried (CaSO₄). CO₂ gas was bubbled through themixture for 10 mins. The mixture was acidified with 1M HCl, diluted withH₂O (40 mL) and extracted with EtOAc (4×30 mL). The combined organicswere dried (Na₂SO₄) and concentrated under reduced pressure to providethe crude product that was further purified by flash chromatography(SiO₂, Hexanes/EtOAc) to afford 26-1 (1.96 g, 51%) as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.4 (br s, COOH, 1H), 7.11 (s, 4H),2.27 (s, 3H), 2.18 (s, 6H).

A solution of 3-(p-tolyl)bicyclo[1.1.1]pentane-1-carboxylic acid (1.0 g,4.94 mmol) in Et₂O (33.0 mL) was treated with methyllithium (1.6M inEt₂O, 6.80 mL, 10.88 mmol) at 0° C. After 15 mins, the ice bath wasremoved, and the mixture was allowed to stir at rt. After 18 h, thereaction was quenched with 3M HCl (aq., 10 mL) and extracted with Et₂O(3×). The combined organic extracts were dried (Na₂SO₄), filtered andconcentrated under pressure to provide 26-2 (900 mg, 91%) as a yellowoil which was used directly in the next step. ¹H NMR (400 MHz, CDCl₃) δ7.13 (s, 4H), 2.33 (s, 3H), 2.27 (s, 6H), 2.19 (s, 3H).

A solution of 1-(3-(p-tolyl)bicyclo[1.1.1]pentan-1-yl)ethanone (500 mg,2.50 mmol) in DCM (1.25 mL) was treated with1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-λ4-sulfanamine (1.66 g, 1.38 mL,7.49 mmol) dropwise at rt. After 2 d at rt, the mixture was diluted withDCM and slowly added to sat. aq. NaHCO₃ (10 mL). The organic layer wasseparated, and the aqueous layer was washed with DCM (2×). The combinedorganic layers were washed with 1M HCl, dried (Na₂SO₄), filtered andconcentrated under reduced pressure to provide crude 26-3 (555 mg, 100%)as a brown oil which was used directly in next step. ¹H NMR (400 MHz,CDCl₃) δ 7.12 (s, 4H), 2.33 (s, 3H), 2.09 (s, 6H), 1.60 (t, J=18.1 Hz,3H).

A solution of crude 1-(1,1-difluoroethyl)-3-phenylbicyclo[1.1.1]pentane(0.275 g, 1.321 mmol) in DCM (2.2 mL):CH₃CN (11 mL):H₂O (11 mL) wastreated with sodium periodate (2.82 g, 13.2 mmol) followed byruthenium(III) chloride trihydrate (35 mg, 0.13 mmol). The reaction wassealed and reacted overnight at rt. The solution was diluted with H₂Oand extracted with CH₂Cl₂ (3×). The combined organics were dried(Na₂SO₄), filtered, and concentrated under reduced pressure to affordthe crude product as a yellow oil. The product was purified by flashchromatography (SiO₂, hexanes/EtOAc) to afford 26-4 (70 mg, 30%) as aclear colorless oil. ¹H-NMR (400 MHz, CDCl₃) δ 2.16 (s, 6H), 1.56 (t,J=18.1 Hz, 3H).

26-4 (70.0 mg, 0.397 mmol) was dissolved in tert-BuOH (2.0 mL). Et₃N (80mg, 0.80 mmol, 0.11 mL) and activated 3 Å molecular sieves were addedfollowed by diphenylphosphoryl azide (103 μL, 0.477 mmol). The solutionwas stirred at 30° C. for 4 h, and then heated to reflux overnight. Thesolution was cooled to rt and then concentrated under reduced pressure.The residual oil was diluted with EtOAc (10 mL) and H₂O (10 mL), andextracted with EtOAc (3×10 mL). The combined organics were dried(Na₂SO₄) and concentrated to afford the crude product that was furtherpurified by flash chromatography (SiO₂, Hexanes/EtOAc) to provide 26-5(33 mg, 34%) as a clear colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 2.08(s, 6H), 1.56 (t, J=18.0 Hz, 3H), 1.45 (s, 9H); ¹⁹F NMR (376 MHz, CDCl₃,unreferenced) δ −96.89.

To a solution of 26-5 (33.0 mg, 0.133 mmol) in EtOAc (1.00 mL) was addedHCl (2 M in Et₂O, 0.388 mL, 1.55 mmol). The solution was stirred at rtovernight. After stirring overnight, the mixture became cloudy withpartial precipitation of the product. Additional HCl (2 M in Et₂O, 0.388mL, 1.55 mmol) was added, and the reaction was stirred overnight. Thesuspension was concentrated, and the residual solid was triturated withEt₂O (2×8 mL). The precipitate was collected by filtration, and thefilter cake was washed with Et₂O (10 mL). The white solid was driedunder vacuum to afford 26 (20.0 mg, 75%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 8.89 (br s, NH, 3H), 2.07 (s, 6H), 1.61 (t, J=118.8 Hz,3H); ¹⁹F NMR (376 MHz, DMSO-d₆, unreferenced) δ −94.62.

Example 27 Compounds of Formula (I) with a Fatty Acid Aliphatic TailGeneral Procedure

A solution of fatty acid in DCM (˜1.1 mL) and DMF (˜0.03-0.12 mL) wascooled to 0° C. and oxalyl chloride (˜0.328-1.31 mmol) was addeddropwise. The mixture was stirred for 1 h followed by the addition of asolution of Compound A in pyridine (˜0.5 mmol). The mixture was warmedto rt and stirred for 30 mins. The mixture was diluted with DCM (5 mL)and washed with 10% aq. HCl and then water. The organic layer was dried(Na₂SO₄), concentrated and purified by flash chromatography (SiO₂,Hexanes/EtOAc) to provide a compound of Formula (I) with a fatty acidaliphatic tail.

The following compounds were prepared using the General Proceduredescribed above and the listed reagents and conditions:

Fatty acid Compound A Product 27 Oleic acid, 99% Capilllary GC (0.056mL, 0.177 mmol)

28 (5Z,8Z,11Z,14Z)- icosa-5,8,11,14- tetraenoic acid (0.054 mL, 0.164mmol)

29 (5Z,8Z,11Z,14Z)- icosa-5,8,11,14- tetraenoic acid (0.054 mL, 0.164mmol)

30 (5Z,8Z,11Z,14Z)- icosa-5,8,11,14- tetraenoic acid (200 mg, 0.58 mmol)

Example 28 Compounds of Formula (I)

For some compounds, the foregoing syntheses are exemplary and can beused as a starting point to prepare additional compounds of Formula (I).Examples of additional compounds of Formula (I) are shown below. Thesecompounds can be prepared in various ways, including those syntheticschemes shown and described herein. Those skilled in the art will beable to recognize modifications of the disclosed syntheses and to deviseroutes based on the disclosures herein; all such modifications andalternate.

Example A Formalin Paw Test

One test compound or the vehicle was administered to each mouse in eachtest group (8 mice per group). Non-fasted male ICR mice weighing 23±3 gwere used. Test compounds were administered at a concentration of 3mg/kg, 10 mg/kg, 15 mg/kg, 30 mg/kg, 60 mg/kg, 100 mg/kg, 200 mg/kg or300 mg/kg; morphine was administered at a concentration of 5 mg/kg; andacetaminophen was administered at a concentration of 200 mg/kg. Thecontrol group received the vehicle (5% DMSO/40% PEG400/20%HPbCD/Saline). After 30 or 60 minutes, a 2% formalin solution (0.02 mL)was injected into one hind paw (sub-plantar) of each mouse. Responseswere measured every 5 minutes after the formalin injection for 35minutes.

Exemplary results are provided in Tables A and B. As shown in Tables Aand B, compounds of Formulae (I) and (II) significantly decreased thepain response in both the early/acute phase (0-10 minutes) and thelate/tonic phase (10-35 minutes). The results in Table A are for oraladministration; the results in Table B are for intraperitonealadministration. In Tables A and B, ‘A’ designates <70 licks/sec, ‘B’designates ≧70 licks/sec and <165 licks/sec, and ‘C’ designates ≧165licks/sec.

TABLE A Dosage Compound No. (mg/kg) Early Phase Late Phase 1 200 A A 2200 B B 3 200 A C 4 200 A C 6 200 B B 8 200 A A 9 200 B C 11 200 A A 12200 B C 14 200 A A

TABLE B Dosage Compound No. (mg/kg) Early Phase Late Phase  3 30 A B 1630 A C 18 30 B C 21 30 B B 22 30 B B 23 30 B C 24 30 B B 25 30 A A 1c 30B B 2d 30 B C

Example B Glutathione Conjugation Assay

An incubation mixture consisting of 5 μL of 10 mM test compound in DMSO(5 μL of DMSO for negative control; 5 μL of 10 mM acetaminophen in DMSOfor positive control), 5 μL of 0.1 μM glutathione 25 mM EDTA in water,50 μL of 100 mM MgCl2 in water, 50 μL of 20 mg/mL pooled human livermicrosomes (P-450 content: ˜0.5 nmol/mg protein), and 340 μL of 100 mMpotassium phosphate buffer (pH 7.4) is preincubated at 37° C. for 10mins. The reaction is initiated by the addition of 50 μL of 100 mM NADPHsolution. The final incubation volume is 0.5 mL. The incubation mixturecontains 100 μM test compound or acetaminophen (positive control), 1 mMglutathione, and 1 μM P450. After 60 mins incubation at 37° C., 1 mL ofchilled acetonitrile is added to stop the reaction. After the additionof acetonitrile, the sample is vortexed and centrifuged. The supernatantis collected, concentrated in TurboVap under N₂ (10 psi) at 30° C. for35 mins, and transferred to a 96-well plate. The plate is capped andcentrifuged. The supernatant is injected for LC-MS/MS analysis.

As described herein, acetaminophen can form the reactive metabolite,N-acetyl-p-benzoquinone imine (NAPQI), which is linked to livertoxicity. Acetaminophen is metabolically activated by cytochrome P450enzymes to form NAPQI, and NAPQI depletes endogenous glutathione (GSH).The depletion of endogenous glutathione leaves cells vulnerable tooxidative damage. The formation of NAPQI is the result of the phenol oraniline ring of acetaminophen.

Unlike acetaminophen, compound of Formulae (I) and/or (II) do notinclude a phenol or aniline ring and it is impossible to connect asubstituent through a double bond (such as a carbonyl or imine group) ateither end of bicyclo[1.1.1]pentane (i.e., at the 1 or 3 positions). Asa result, one skilled in the art would not expect compounds of Formulae(I) and/or (II) to form the reactive metabolite NAPQI. A 129 neutralloss scan can be used to search or detect the formation of glutathioneconjugates of reactive metabolites.

Although the foregoing has been described in some detail by way ofillustrations and examples for purposes of clarity and understanding, itwill be understood by those of skill in the art that numerous andvarious modifications can be made without departing from the spirit ofthe present disclosure. Therefore, it should be clearly understood thatthe forms disclosed herein are illustrative only and are not intended tolimit the scope of the present disclosure, but rather to also cover allmodification and alternatives coming with the true scope and spirit ofthe invention.

1. A method for reducing or at least partially preventing pain or fevercomprising contacting a cell in the central and/or peripheral nervoussystem of a subject with an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, in a subject in needthereof, wherein Formula (I) has the structure:

wherein: R¹ is selected from the group consisting of H, D, a substitutedor unsubstituted C₁₋₆ alkyl and a substituted or unsubstituted C₁₋₆haloalkyl; R² is H or C(═O)R^(2A); R^(2A) is selected from the groupconsisting of H, D, a substituted or unsubstituted C₁₋₃₀ alkyl, asubstituted or unsubstituted C₂₋₃₀ alkenyl, a substituted orunsubstituted C₂₋₃₀ alkynyl, a substituted or unsubstituted C₃₋₃₀cycloalkyl, a substituted or unsubstituted C₃₋₃₀ cycloalkenyl, asubstituted or unsubstituted C₈₋₃₀ cycloalkynyl, a substituted orunsubstituted C₆₋₃₀ aryl, a substituted or unsubstituted heteroaryl, asubstituted or unsubstituted heterocyclyl, a substituted orunsubstituted aryl(C₁₋₆ alkyl), a substituted or unsubstitutedheteroaryl(C₁₋₆ alkyl), a substituted or unsubstituted heterocyclyl(C₁₋₆alkyl) and a substituted or unsubstituted C₁₋₈ haloalkyl; R³ is selectedfrom the group consisting of H, D, halo, hydroxy, a substituted orunsubstituted C₁₋₈ alkyl, a substituted or unsubstituted C₂₋₈ alkenyl, asubstituted or unsubstituted C₂₋₈ alkynyl, a substituted orunsubstituted C₃₋₂₀ cycloalkyl, a substituted or unsubstituted C₃₋₂₀cycloalkenyl, a substituted or unsubstituted C₈₋₂₀ cycloalkynyl, asubstituted or unsubstituted C₆₋₂₀ aryl, a substituted or unsubstitutedheteroaryl, a substituted or unsubstituted heterocyclyl, a substitutedor unsubstituted aryl(C₁₋₆ alkyl), a substituted or unsubstitutedheteroaryl(C₁₋₆ alkyl), a substituted or unsubstituted heterocyclyl(C₁₋₆alkyl), a substituted or unsubstituted C₁₋₈ haloalkyl and a substitutedor unsubstituted sulfonyl; A¹ is CR⁴R⁵; R⁴ and R⁵ are independentlyselected from the group consisting of H, D, an unsubstituted C₁₋₈ alkyland an unsubstituted C₁₋₆ haloalkyl, or R⁴ and R⁵ are taken together toform an optionally substituted C₃₋₆ cycloalkyl; and m is 0, 1, 2 or 3;and provided that when m is 0, R¹ and R² are each H, then R³ is nott-butyl; and a compound of Formula (I), or a pharmaceutically saltthereof is not


2. The method of claim 1, wherein R¹ is H or an unsubstituted C₁₋₆alkyl.
 3. (canceled)
 4. (canceled)
 5. (canceled)
 6. (canceled) 7.(canceled)
 8. The method of claim 1, wherein R² is H.
 9. The method ofclaim 1, wherein R² is C(═O)R^(2A).
 10. (canceled)
 11. (canceled) 12.The method of claim 9, wherein R^(2A) is a substituted or unsubstitutedC₁₋₃₀ alkyl.
 13. (canceled)
 14. The method of claim 12, wherein R^(2A)is selected from the group consisting of —(CH₂)₆CH₃, —(CH₂)₈CH₃,—(CH₂)₁₀CH₃, —(CH₂)₁₂CH₃, —(CH₂)₁₄CH₃, —(CH₂)₁₆CH₃, —(CH₂)₁₈CH₃,—(CH₂)₂₀CH₃, —(CH₂)₂₂CH₃ and —(CH₂)₂₄CH₃.
 15. The method of claim 9,wherein R^(2A) is a substituted or unsubstituted C₂₋₃₀ alkenyl. 16.(canceled)
 17. The method of claim 15, wherein R^(2A) is selected fromthe group consisting of —(CH₂)₇CH═CH(CH₂)₃CH₃,—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃, —(CH₂)₇CH═CH(CH₂)₇CH₃,—(CH₂)₇CH═CHCH₂CH═CH(CH₂)₄CH₃, —(CH₂)₇CH═CH(CH₂)₇CH₃,—(CH₂)₇CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃, —(CH₂)₉CH═CH(CH₂)₅CH₃,—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₄CH₃, —(CH₂)₁₁CH═CH(CH₂)₇CH₃,—(CH₂)₃CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃, (CH₂)₄CH═CHCH(CH₃)₂and —(CH₂)₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH₃.
 18. Themethod of claim 9, wherein R^(2A) is a substituted or unsubstitutedC₂₋₃₀ alkynyl, a substituted or unsubstituted C₃₋₃₀ cycloalkyl, asubstituted or unsubstituted C₃₋₃₀ cycloalkenyl, a substituted orunsubstituted C₈₋₃₀ cycloalkynyl, a substituted or unsubstituted C₆₋₃₀aryl, a substituted or unsubstituted heteroaryl, a substituted orunsubstituted heterocyclyl, a substituted or unsubstituted aryl(C₁₋₆alkyl), a substituted or unsubstituted heteroaryl(C₁₋₆ alkyl), asubstituted or unsubstituted heterocyclyl(C₁₋₆ alkyl) and a substitutedor unsubstituted C₁₋₈ haloalkyl. 19.-43. (canceled)
 44. The method ofclaim 1, wherein R³ is H.
 45. (canceled)
 46. The method of claim 1,wherein R³ is halo.
 47. (canceled)
 48. (canceled)
 49. (canceled)
 50. Themethod of claim 1, wherein R³ is a substituted or unsubstituted C₁₋₈alkyl, a substituted or unsubstituted (C₃₋₂₀ cycloalkyl, a substitutedor unsubstituted C₁₋₈ haloalkyl and a substituted or unsubstitutedsulfonyl.
 51. (canceled)
 52. The method of claim 1, wherein R³ is asubstituted or unsubstituted C₂₋₈ alkenyl, a substituted orunsubstituted C₂₋₈ alkynyl, a substituted or unsubstituted C₃₋₂₀cycloalkenyl, a substituted or unsubstituted C₈₋₂₀ cycloalkynyl, asubstituted or unsubstituted C₆₋₂₀ aryl, a substituted or unsubstitutedheteroaryl, a substituted or unsubstituted heterocyclyl, a substitutedor unsubstituted aryl(C₁₋₆ alkyl), a substituted or unsubstitutedheteroaryl(C₁₋₆ alkyl) and a substituted or unsubstitutedheterocyclyl(C₁₋₆ alkyl). 53.-81. (canceled)
 82. The method of claim 1,wherein m is
 0. 83. The method of claim 1, wherein m is 1; A¹ is CR⁴R⁵;R⁴ is H and R⁵ is H.
 84. The method of claim 1, wherein m is 2 or 3;each A¹ is CR⁴R⁵; each R⁴ is H and each R⁵ is H. 85.-96. (canceled) 97.The method of claim 1, wherein the compound is selected from

or a pharmaceutically acceptable salt of the foregoing.
 98. The methodof claim 1, wherein the compound is selected from

or a pharmaceutically acceptable salt of the foregoing.
 99. The methodof claim 1, wherein the compound is selected from

or a pharmaceutically acceptable salt of the foregoing.
 100. The methodof claim 1, further comprising an opioid analgesic. 101.-119. (canceled)120. A compound of Formula (II), or a pharmaceutically acceptable saltthereof:

wherein: R^(1b) is H or CH₃; R^(2b) is CH₂F, CHF₂, CF₃ or anunsubstituted C₁₋₄ alkyl; and R^(3b) is H, CH₂F, CHF₂, CF₃, anunsubstituted C₁₋₄ alkyl or a hydro-substituted C₁₋₄ alkyl. 121.-132.(canceled)
 133. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt of the foregoing.
 134. (canceled)135. A method for reducing or at least partially preventing pain orfever comprising administering an effective amount of a compound ofclaim 120, to a subject in need thereof. 136.-156. (canceled)
 157. Acompound of Formula (I), or a pharmaceutically acceptable salt thereof,as recited in claim 1, provided that when m is 0, then R² is H; providedthat when m is 0, R¹ is H, and R² is H, then R³ is not selected from thegroup consisting of H, CH₃, F, I, hydroxy, unsubstituted t-butyl,unsubstituted phenyl, an optionally substituted bicyclo[1.1.1]pentaneand CF₃; and provided that a compound of Formula (I) cannot beN,N-diethyl-alpha-methyl-bicyclo[1.1.1]pentane-1-methanamine or


158. A pharmaceutical composition comprising an effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,as recited in claim 157, and a pharmaceutically acceptable carrier,diluent, excipient or combination thereof.